Modeling the behavior of uveal melanoma in the liver.

PURPOSE: To model the behavior of uveal melanoma in the liver. METHODS: A 15-muL suspension of metastatic MUM2B or either primary OCM1 or M619 uveal melanoma cells was injected into the liver parenchyma of 105 CB17 SCID mice through a 1-cm abdominal incision. Animals were killed at 2, 4, 6, or 8 weeks after injection. Before euthanatization, 3% FITC-BSA buffer was injected into the retro-orbital plexus of one eye of three mice. Liver tissues were examined by light and fluorescence microscopy, and were stained with human anti-laminin. Vasculogenic mimicry patterns were reconstructed from serial laser scanning confocal microscopic stacks. RESULTS: OCM1a cells formed microscopic nodules in the mouse liver within 2 weeks after injection and metastasized to the lung 6 weeks later. By contrast, M619 and MUM2B cells formed expansile nodules in the liver within 2 weeks and gave rise to pulmonary metastases within 4 weeks after injection. Vasculogenic mimicry patterns, composed of human laminin and identical with those in human primary and metastatic uveal melanomas, were detected in the animal model. The detection of human rather than mouse laminin in the vasculogenic mimicry patterns in this model demonstrates that these patterns were of tumor cell origin and were not co-opted from the mouse liver microenvironment. CONCLUSIONS: There are currently no effective treatments for metastatic uveal melanoma. This direct-injection model focuses on critical interactions between the tumor cell and the liver. It provides for translationally relevant approaches to the development of new modalities to detect small tumor burdens in patients, to study the biology of clinical dormancy of metastatic disease in uveal melanoma, to design and test novel treatments to prevent the emergence of clinically manifest liver metastases after dormancy, and to treat established uveal melanoma metastases.

Comparing vasculogenic mimicry with endothelial cell-lined vessels: techniques for 3D reconstruction and quantitative analysis of tissue components from archival paraffin blocks.

We previously described techniques to generate 3-dimensional reconstructions of the tumor microcirculation using immunofluorescence histochemistry and laser scanning confocal microscopy on serial sections from archival formalin-fixed, paraffin-embedded tissues. By aligning sequential z-stacks in an immersive visualization environment (ImmersaDesk), the need to insert fiduciary markers into tissue was eliminated. In this study, we developed methods to stitch overlapping confocal z-series together to extend the surface area of interest well beyond that captured by the confocal microscope objective and developed methods to quantify the distribution of markers of interest in 3 dimensions. These techniques were applied to the problem of comparing the surface area of nonendothelial cell-lined, laminin-rich looping vasculogenic mimicry (VM) patterns that are known to transmit fluid, with the surface area of endothelial cell-lined vessels in metastatic uveal melanoma to the liver in 3 dimensions. After labeling sections with antibodies to CD34 and laminin, the surface area of VM patterns to vessels was calculated by segmenting out structures that labeled with laminin but not with CD34 from those structures labeling with CD34, or CD34 and laminin. In metastatic uveal melanoma tissues featuring colocalization of high microvascular density [66.4 microvessels adjusted for 0.313 mm2 area (range 56.7 to 72.7)] and VM patterning, the surface area of VM patterns was 11.6-fold greater (range 10.8 to 14.1) than the surface provided by CD34-positive vessels. These methods may be extended to visualize and quantify molecular markers in 3 dimensions in a variety of pathologic entities from archival paraffin-embedded tissues.

Visualization of large-scale confocal data using computer cluster.

A virtual reality system with remote computer cluster for interactive three-dimensional reconstruction and alignment of large confocal microscopy data is presented. It provides the flexibility and the accumulated power of computer cluster for this specific application.

Cranial implant design using augmented reality immersive system.

Software tools that utilize haptics for sculpting precise fitting cranial implants are utilized in an augmented reality immersive system to create a virtual working environment for the modelers. The virtual environment is designed to mimic the traditional working environment as closely as possible, providing more functionality for the users. The implant design process uses patient CT data of a defective area. This volumetric data is displayed in an implant modeling tele-immersive augmented reality system where the modeler can build a patient specific implant that precisely fits the defect. To mimic the traditional sculpting workspace, the implant modeling augmented reality system includes stereo vision, viewer centered perspective, sense of touch, and collaboration. To achieve optimized performance, this system includes a dual-processor PC, fast volume rendering with three-dimensional texture mapping, the fast haptic rendering algorithm, and a multi-threading architecture. The system replaces the expensive and time consuming traditional sculpting steps such as physical sculpting, mold making, and defect stereolithography. This augmented reality system is part of a comprehensive tele-immersive system that includes a conference-room-sized system for tele-immersive small group consultation and an inexpensive, easily deployable networked desktop virtual reality system for surgical consultation, evaluation and collaboration. This system has been used to design patient-specific cranial implants with precise fit.

New tools for sculpting cranial implants in a shared haptic augmented reality environment.

New volumetric tools were developed for the design and fabrication of high quality cranial implants from patient CT data. These virtual tools replace time consuming physical sculpting, mold making and casting steps. The implant is designed by medical professionals in tele-immersive collaboration. Virtual clay is added in the virtual defect area on the CT data using the adding tool. With force feedback the modeler can feel the edge of the defect and fill only the space where no bone is present. A carving tool and a smoothing tool are then used to sculpt and refine the implant. To make a physical evaluation, the skull with simulated defect and the implant are fabricated via stereolithography to allow neurosurgeons to evaluate the quality of the implant. Initial tests demonstrate a very high quality fit. These new haptic volumetric sculpting tools are a critical component of a comprehensive tele-immersive system.

Reconstruction and exploration of three-dimensional confocal microscopy data in an immersive virtual environment.

An immersive virtual environment for interactive three-dimensional reconstruction and exploration of confocal microscopy data is presented. For some structures automatic alignment of serial sections can lead to geometric distortions. The superior visual feedback of a Virtual Reality system is used to aid in registering and aligning serial sections interactively. An ImmersaDesk Virtual Reality display system is used for display and interaction with the volumetric confocal data. Detailed methods for handling both single-section and multi-section confocal data are described.

Desktop and conference room VR for physicians.

Virtual environments such as the CAVE and the ImmersaDesk, which are based on graphics supercomputers or workstations, are large and expensive. Most physicians have no access to such systems. The recent development of small Linux personal computers and high-performance graphics cards has afforded opportunities to implement applications formerly run on graphics supercomputers. Using PC hardware and other affordable devices, a VR system has been developed which can sit on a physician's desktop or be installed in a conference room. Affordable PC-based VR systems are comparable in performance with expensive VR systems formerly based on graphics supercomputers. Such VR systems can now be accessible to most physicians. The lower cost and smaller size of this system greatly expands the range of uses of VR technology in medicine.

Simulation of color deficiency in virtual reality.

Color deficiency protanopia is simulated in a virtual home environment. A color database is created to set the corresponding relation between each color for normal vision and for protanopia. Based on this database, a second texture system is set up for the home model. The proper texture system is used according to the user's choice on the interactive menu.

Three-dimensional reconstruction of extravascular matrix patterns and blood vessels in human uveal melanoma tissue: techniques and preliminary findings.

PURPOSE: Looping patterns rich in laminin are present in tissue samples of primary aggressive human uveal melanomas and their metastases. Because these extravascular patterns connect to blood vessels and transmit fluid in vitro and in vivo, the three-dimensional configuration of these patterns has been the subject of considerable speculation. In the current study, methods were devised to describe the three-dimensional configuration of looping extravascular matrix patterns in archival human uveal melanoma tissue. METHODS: Twenty-five serial 4-microm-thick sections from primary uveal melanoma tissue were labeled with fluorescence-tagged laminin and examined by confocal microscopy to generate a Z-series within each 4-microm-thick section. The z-series from each section was stacked using an immersive three-dimensional environment (ImmersaDesk; Fakespace, Kitchener, Ontario, Canada) to allow for precise alignment and compensation for distortion artifact. RESULTS: Extravascular matrix patterns that appeared to form loops in two dimensions were shown to represent thin wrappings around branching and twisting cylindrical groupings of melanoma cells. Blood vessels joined with some of these laminin-positive cylindrical wrappings. CONCLUSIONS: In this preliminary study, periodic acid-Schiff (PAS)-positive laminin-rich looping patterns in two-dimensional tissue sections appear to outline cylindrical branching packets of melanoma cells rather than spheroidal nests. The conduction of fluid through this extravascular system may provide a novel delivery system for contrast and diagnostic agents.

The virtual nose: a 3-dimensional virtual reality model of the human nose.

BACKGROUND: The 3-dimensionally complex interplay of soft tissue, cartilaginous, and bony elements makes the mastery of nasal anatomy difficult. Conventional methods of learning nasal anatomy exist, but they often involve a steep learning curve. Computerized models and virtual reality applications have been used to facilitate teaching in a number of other complex anatomical regions, such as the human temporal bone and pelvic floor. We present a 3-dimensional (3-D) virtual reality model of the human nose. METHODS: Human cadaveric axial cross-sectional (0.33-mm cuts) photographic data of the head and neck were used. With 460 digitized images, individual structures were traced and programmed to create a computerized polygonal model of the nose. Further refinements to this model were made using a number of specialized computer programs. This 3-D computer model of the nose was then programmed to operate as a virtual reality model. RESULTS: Anatomically correct 3-D model of the nose was produced. High-resolution images of the "virtual nose" demonstrate the nasal septum, lower lateral cartilages, middle vault, bony dorsum, and other structural details of the nose. Also, the model can be combined with a separate virtual reality model of the face and its skin cover as well as the skull. The user can manipulate the model in space, examine 3-D anatomical relationships, and fade superficial structures to reveal deeper ones. CONCLUSIONS: The virtual nose is a 3-D virtual reality model of the nose that is accurate and easy to use. It can be run on a personal computer or in a specialized virtual reality environment. It can serve as an effective teaching tool. As the first virtual reality model of the nose, it establishes a virtual reality platform from which future applications can be launched.

Tele-Immersive medical educational environment.

By combining teleconferencing, tele-presence, and Virtual Reality, the Tele-Immersive environment enables master surgeons to teach residents in remote locations. The design and implementation of a Tele-Immersive medical educational environment, Teledu, is presented in this paper. Teledu defines a set of Tele-Immersive user interfaces for medical education. In addition, an Application Programming Interface (API) is provided so that developers can easily develop different applications with different requirements in this environment. With the help of this API, programmers only need to design a plug-in to load their application specific data set. The plug-in is an object-oriented data set loader. Methods for rendering, handling, and interacting with the data set for each application can be programmed in the plug-in. The environment has a teacher mode and a student mode. The teacher and the students can interact with the same medical models, point, gesture, converse, and see each other.

Evaluation of Multivariate Visualization on a Multivariate Task.

Multivariate visualization techniques have attracted great interest as the dimensionality of data sets grows. One premise of such techniques is that simultaneous visual representation of multiple variables will enable the data analyst to detect patterns amongst multiple variables. Such insights could lead to development of new techniques for rigorous (numerical) analysis of complex relationships hidden within the data. Two natural questions arise from this premise: Which multivariate visualization techniques are the most effective for high-dimensional data sets? How does the analysis task change this utility ranking? We present a user study with a new task to answer the first question. We provide some insights to the second question based on the results of our study and results available in the literature. Our task led to significant differences in error, response time, and subjective workload ratings amongst four visualization techniques. We implemented three integrated techniques (Data-driven Spots, Oriented Slivers, and Attribute Blocks), as well as a baseline case of separate grayscale images. The baseline case fared poorly on all three measures, whereas Datadriven Spots yielded the best accuracy and was among the best in response time. These results differ from comparisons of similar techniques with other tasks, and we review all the techniques, tasks, and results (from our work and previous work) to understand the reasons for this discrepancy.

Haptic rendering of volumetric data for cranial implant modeling.

A force feedback algorithm for cranial implant design is presented in this paper. The algorithm is applied directly on volumetric data. It is a proxy-based algorithm, and a spherical proxy is used to accurately calculate the force between the sculpting tool and the skull. Based on this algorithm a cranial implant modeling system is implemented, and an implant for a simulated defect is designed.

Simulation of eye disease in virtual reality.

It is difficult to understand verbal descriptions of visual phenomenon if one has no such experience. Virtual Reality offers a unique opportunity to "experience" diminished vision and the problems it causes in daily life. We have developed an application to simulate age-related macular degeneration, glaucoma, protanopia, and diabetic retinopathy in a familiar setting. The application also includes the introduction of eye anatomy representing both normal and pathologic states. It is designed for patient education, health care practitioner training, and eye care specialist education.

Virtual reality: new method of teaching anorectal and pelvic floor anatomy.

PURPOSE: A clear understanding of the intricate spatial relationships among the structures of the pelvic floor, rectum, and anal canal is essential for the treatment of numerous pathologic conditions. Virtual-reality technology allows improved visualization of three-dimensional structures over conventional media because it supports stereoscopic-vision, viewer-centered perspective, large angles of view, and interactivity. We describe a novel virtual reality-based model designed to teach anorectal and pelvic floor anatomy, pathology, and surgery. METHODS: A static physical model depicting the pelvic floor and anorectum was created and digitized at 1-mm intervals in a CT scanner. Multiple software programs were used along with endoscopic images to generate a realistic interactive computer model, which was designed to be viewed on a networked, interactive, virtual-reality display (CAVE or ImmersaDesk). A standard examination of ten basic anorectal and pelvic floor anatomy questions was administered to third-year (n = 6) and fourth-year (n = 7) surgical residents. A workshop using the Virtual Pelvic Floor Model was then given, and the standard examination was readministered so that it was possible to evaluate the effectiveness of the Digital Pelvic Floor Model as an educational instrument. RESULTS: Training on the Virtual Pelvic Floor Model produced substantial improvements in the overall average test scores for the two groups, with an overall increase of 41 percent (P = 0.001) and 21 percent (P = 0.0007) for third-year and fourth-year residents, respectively. Resident evaluations after the workshop also confirmed the effectiveness of understanding pelvic anatomy using the Virtual Pelvic Floor Model. CONCLUSION: This model provides an innovative interactive educational framework that allows educators to overcome some of the barriers to teaching surgical and endoscopic principles based on understanding highly complex three-dimensional anatomy. Using this collaborative, shared virtual-reality environment, teachers and students can interact from locations world-wide to manipulate the components of this model to achieve the educational goals of this project along with the potential for virtual surgery.