The development of decision support systems for pathology and their deployment in clinical practice have been hindered by the need for large manually annotated datasets. To overcome this problem, we ...present a multiple instance learning-based deep learning system that uses only the reported diagnoses as labels for training, thereby avoiding expensive and time-consuming pixel-wise manual annotations. We evaluated this framework at scale on a dataset of 44,732 whole slide images from 15,187 patients without any form of data curation. Tests on prostate cancer, basal cell carcinoma and breast cancer metastases to axillary lymph nodes resulted in areas under the curve above 0.98 for all cancer types. Its clinical application would allow pathologists to exclude 65-75% of slides while retaining 100% sensitivity. Our results show that this system has the ability to train accurate classification models at unprecedented scale, laying the foundation for the deployment of computational decision support systems in clinical practice.
Context Augmented reality (AR) devices such as the Microsoft HoloLens have not been well used in the medical field. Objective To test the HoloLens for clinical and nonclinical applications in ...pathology. Design A Microsoft HoloLens was tested for virtual annotation during autopsy, viewing 3D gross and microscopic pathology specimens, navigating whole slide images, telepathology, as well as real-time pathology-radiology correlation. Results Pathology residents performing an autopsy wearing the HoloLens were remotely instructed with real-time diagrams, annotations, and voice instruction. 3D-scanned gross pathology specimens could be viewed as holograms and easily manipulated. Telepathology was supported during gross examination and at the time of intraoperative consultation, allowing users to remotely access a pathologist for guidance and to virtually annotate areas of interest on specimens in real-time. The HoloLens permitted radiographs to be coregistered on gross specimens and thereby enhanced locating important pathologic findings. The HoloLens also allowed easy viewing and navigation of whole slide images, using an AR workstation, including multiple coregistered tissue sections facilitating volumetric pathology evaluation. Conclusions The HoloLens is a novel AR tool with multiple clinical and nonclinical applications in pathology. The device was comfortable to wear, easy to use, provided sufficient computing power, and supported high-resolution imaging. It was useful for autopsy, gross and microscopic examination, and ideally suited for digital pathology. Unique applications include remote supervision and annotation, 3D image viewing and manipulation, telepathology in a mixed-reality environment, and real-time pathology-radiology correlation.
Pathology laboratories are undergoing digital transformations, adopting innovative technologies to enhance patient care. Digital pathology systems impact clinical, education, and research use cases ...where pathologists use digital technologies to perform tasks in lieu of using glass slides and a microscope. Pathology professional societies have established clinical validation guidelines, and the US Food and Drug Administration have also authorized digital pathology systems for primary diagnosis, including image analysis and machine learning systems. Whole slide images, or digital slides, can be viewed and navigated similar to glass slides on a microscope. These modern tools not only enable pathologists to practice their routine clinical activities, but can potentially enable digital computational discovery. Assimilation of whole slide images in pathology clinical workflow can further empower machine learning systems to support computer assisted diagnostics. The potential enrichment these systems can provide is unprecedented in the field of pathology. With appropriate integration, these clinical decision support systems will allow pathologists to increase the delivery of quality patient care. This review describes the digital pathology transformation process, applicable clinical use cases, incorporation of image analysis and machine learning systems in the clinical workflow, as well as future technologies that may further disrupt pathology modalities to deliver quality patient care.
Whole Slide Imaging: Technology and Applications Hanna, Matthew G; Parwani, Anil; Sirintrapun, Sahussapont Joseph
Advances in anatomic pathology,
2020-July, Volume:
27, Issue:
4
Journal Article
Peer reviewed
Pathology has benefited from advanced innovation with novel technology to implement a digital solution. Whole slide imaging is a disruptive technology where glass slides are scanned to produce ...digital images. There have been significant advances in whole slide scanning hardware and software that have allowed for ready access of whole slide images. The digital images, or whole slide images, can be viewed comparable to glass slides in a microscope, as digital files. Whole slide imaging has increased in adoption among pathologists, pathology departments, and scientists for clinical, educational, and research initiatives. Worldwide usage of whole slide imaging has grown significantly. Pathology regulatory organizations (ie, College of American Pathologists) have put forth guidelines for clinical validation, and the US Food and Drug Administration have also approved whole slide imaging for primary diagnosis. This article will review the digital pathology ecosystem and discuss clinical and nonclinical applications of its use.
Effectively conserving ecosystem services in order to maintain human wellbeing is a global need that requires an understanding of where ecosystem services are produced by ecosystems and where people ...benefit from these services. However, approaches to effectively identify key locations that have the capacity to supply ecosystem services and actually contribute to meeting human demand for those services are lacking at broad spatial scales. We developed new methods that integrate measures of the capacity of ecosystems to provide services with indicators of human demand and ability to access these services. We then identified important areas for three ecosystem services currently central to protected area management in Canada-carbon storage, freshwater, and nature-based recreation-and evaluated how these hotspots align with Canada's current protected areas and resource development tenures. We find that locations of ecosystem service capacity overlap only weakly (27-36%) with actual service providing areas (incorporating human access and demand). Overlapping hotspots of provision for multiple ecosystem services are also extremely limited across Canada; only 1.2% (∼56 000 km2) of the total ecosystem service hotspot area in Canada consists of overlap between all three ecosystem services. Canada's current protected area network also targets service capacity to a greater degree than provision. Finally, one-half to two-thirds of current ecosystem service hotspots (54-66%) overlap with current and planned resource extraction activities. Our analysis demonstrates how to identify areas where conservation and ecosystem service management actions should be focused to more effectively target ecosystem services to ensure that critical areas for ecosystem services that directly benefit people are conserved. Further development of these methods at national scales to assess ecosystem service capacity and demand and integrate this with conventional biodiversity and conservation planning information will help ensure that both biodiversity and ecosystem services are effectively safeguarded.
Remote digital pathology allows healthcare systems to maintain pathology operations during public health emergencies. Existing Clinical Laboratory Improvement Amendments regulations require ...pathologists to electronically verify patient reports from a certified facility. During the 2019 pandemic of COVID-19 disease, caused by the SAR-CoV-2 virus, this requirement potentially exposes pathologists, their colleagues, and household members to the risk of becoming infected. Relaxation of government enforcement of this regulation allows pathologists to review and report pathology specimens from a remote, non-CLIA certified facility. The availability of digital pathology systems can facilitate remote microscopic diagnosis, although formal comprehensive (case-based) validation of remote digital diagnosis has not been reported. All glass slides representing routine clinical signout workload in surgical pathology subspecialties at Memorial Sloan Kettering Cancer Center were scanned on an Aperio GT450 at ×40 equivalent resolution (0.26 µm/pixel). Twelve pathologists from nine surgical pathology subspecialties remotely reviewed and reported complete pathology cases using a digital pathology system from a non-CLIA certified facility through a secure connection. Whole slide images were integrated to and launched within the laboratory information system to a custom vendor-agnostic, whole slide image viewer. Remote signouts utilized consumer-grade computers and monitors (monitor size, 13.3–42 in.; resolution, 1280 × 800–3840 × 2160 pixels) connecting to an institution clinical workstation via secure virtual private network. Pathologists subsequently reviewed all corresponding glass slides using a light microscope within the CLIA-certified department. Intraobserver concordance metrics included reporting elements of top-line diagnosis, margin status, lymphovascular and/or perineural invasion, pathology stage, and ancillary testing. The median whole slide image file size was 1.3 GB; scan time/slide averaged 90 s; and scanned tissue area averaged 612 mm2. Signout sessions included a total of 108 cases, comprised of 254 individual parts and 1196 slides. Major diagnostic equivalency was 100% between digital and glass slide diagnoses; and overall concordance was 98.8% (251/254). This study reports validation of primary diagnostic review and reporting of complete pathology cases from a remote site during a public health emergency. Our experience shows high (100%) intraobserver digital to glass slide major diagnostic concordance when reporting from a remote site. This randomized, prospective study successfully validated remote use of a digital pathology system including operational feasibility supporting remote review and reporting of pathology specimens, and evaluation of remote access performance and usability for remote signout.
The field of anatomic pathology has been evolving in the last few decades and the advancements have been largely fostered by innovative technology. Immunohistochemistry enabled a paradigm shift in ...discovery and diagnostic evaluation, followed by booming genomic advancements which allowed for submicroscopic pathologic characterization, and now the field of digital pathology coupled with machine learning and big data acquisition is paving the way to revolutionize the pathology medical domain. Whole slide imaging (WSI) is a disruptive technology where glass slides are digitized to produce on-screen whole slide images. Specifically, in the past decade, there have been significant advances in digital pathology systems that have allowed this technology to promote integration into clinical practice. Whole slide images (WSI), or digital slides, can be viewed and navigated comparable to glass slides on a microscope, as digital files. Whole slide imaging has increased in adoption among pathologists, pathology departments, and scientists for clinical, educational, and research initiatives. Integration of digital pathology systems requires a coordinated effort with numerous stakeholders, not only within the pathology department, but across the entire enterprise. Each pathology department has distinct needs, use cases and blueprints, however the framework components and variables for successful clinical integration can be generalized across any organization seeking to undergo a digital transformation at any scale. This article will review those components and considerations for integrating digital pathology systems into clinical practice.
Core needle biopsy (CNB) of breast lesions is routine for diagnosis and treatment planning. Despite refinement of diagnostic criteria, the diagnosis of breast lesions on CNB can be challenging. At ...many centers, including ours, confirmation of diagnoses rendered in other laboratories is required before treatment planning. We identified CNBs first diagnosed elsewhere that were reviewed in our department over the course of 1 year because the patients sought care at our center and in which a change in diagnosis had been recorded. The outside and in-house CNB diagnoses were then classified based on Breast WHO Fifth Edition diagnostic categories. The impact of the change in diagnosis was estimated based on the subsequent surgical management. Findings in follow-up surgical excisions (EXCs) were used for validation. In 2018, 4950 outside cases with CNB were reviewed at our center. A total of 403 CNBs diagnoses were discrepant. Of these, 147 had a change in the WHO diagnostic category: 80 (54%) CNBs had a more severe diagnosis and 44 (30%) a less severe diagnosis. In 23 (16%) CNBs, the change of diagnostic category had no impact on management. Intraductal proliferations (n=54), microinvasive carcinoma (n=18), and papillary lesions (n=35) were the most disputed diagnoses. The in-house CNB diagnosis was confirmed in most cases with available excisions. Following CNB reclassification, 22/147 (15%) lesions were not excised. A change affecting the surgical management at our center occurred in 2.5% of all CNBs. Our results support routine review of outside breast CNB as a clinically significant practice before definitive treatment.
Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory ...signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells.
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Spectrally-resolved single-molecule localization microscopy (srSMLM) has emerged as a powerful tool for exploring the spectral properties of single emitters in localization microscopy. By ...simultaneously capturing the spatial positions and spectroscopic signatures of individual fluorescent molecules, srSMLM opens up the possibility of investigating an additional dimension in super-resolution imaging. However, appropriate and dedicated tools are required to fully capitalize on the spectral dimension. Here, we propose the application of the spectral phasor analysis as an effective method for summarizing and analyzing the spectral information obtained from srSMLM experiments. The spectral phasor condenses the complete spectrum of a single emitter into a two-dimensional space, preserving key spectral characteristics for single-molecule spectral exploration. We demonstrate the effectiveness of spectral phasor in efficiently classifying single Nile Red fluorescence emissions from largely overlapping cyanine fluorescence signals in dual-color PAINT experiments. Additionally, we employed spectral phasor with srSMLM to reveal subtle alterations occurring in the membrane of Gram-positive Enterococcus hirae in response to gramicidin exposure, a membrane-perturbing antibiotic treatment. Spectral phasor provides a robust, model-free analytic tool for the detailed analysis of the spectral component of srSMLM, enhancing the capabilities of multi-color spectrally-resolved single-molecule imaging.
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