PanIN or IPMN? Redefining Lesion Size in 3 Dimensions.

Pancreatic ductal adenocarcinoma (PDAC) develops from 2 known precursor lesions: a majority (∼85%) develops from pancreatic intraepithelial neoplasia (PanIN), and a minority develops from intraductal papillary mucinous neoplasms (IPMNs). Clinical classification of PanIN and IPMN relies on a combination of low-resolution, 3-dimensional (D) imaging (computed tomography, CT), and high-resolution, 2D imaging (histology). The definitions of PanIN and IPMN currently rely heavily on size. IPMNs are defined as macroscopic: generally >1.0 cm and visible in CT, and PanINs are defined as microscopic: generally <0.5 cm and not identifiable in CT. As 2D evaluation fails to take into account 3D structures, we hypothesized that this classification would fail in evaluation of high-resolution, 3D images. To characterize the size and prevalence of PanINs in 3D, 47 thick slabs of pancreas were harvested from grossly normal areas of pancreatic resections, excluding samples from individuals with a diagnosis of an IPMN. All patients but one underwent preoperative CT scans. Through construction of cellular resolution 3D maps, we identified >1400 ductal precursor lesions that met the 2D histologic size criteria of PanINs. We show that, when 3D space is considered, 25 of these lesions can be digitally sectioned to meet the 2D histologic size criterion of IPMN. Re-evaluation of the preoperative CT images of individuals found to possess these large precursor lesions showed that nearly half are visible on imaging. These findings demonstrate that the clinical classification of PanIN and IPMN fails in evaluation of high-resolution, 3D images, emphasizing the need for re-evaluation of classification guidelines that place significant weight on 2D assessment of 3D structures.

3D genomic mapping reveals multifocality of human pancreatic precancers.

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.

Three-dimensional assessments are necessary to determine the true, spatially-resolved composition of tissues.

Methods for spatially resolved cellular profiling using thinly cut sections have enabled in-depth quantitative tissue mapping to study inter-sample and intra-sample differences in normal human anatomy and disease onset and progression. These methods often profile extremely limited regions, which may impact the evaluation of heterogeneity due to tissue sub-sampling. Here, we applied CODA, a deep learning-based tissue mapping platform, to reconstruct the three-dimensional (3D) microanatomy of grossly normal and cancer-containing human pancreas biospecimens obtained from individuals who underwent pancreatic resection. To compare inter- and intra-sample heterogeneity, we assessed bulk and spatially resolved tissue composition in a cohort of two-dimensional (2D) whole slide images (WSIs) and a cohort of thick slabs of pancreas tissue that were digitally reconstructed in 3D from serial sections. To demonstrate the marked under sampling of 2D assessments, we simulated the number of WSIs and tissue microarrays (TMAs) necessary to represent the compositional heterogeneity of 3D data within 10% error to reveal that tens of WSIs and hundreds of TMA cores are sometimes needed. We show that spatial correlation of different pancreatic structures decay significantly within a span of microns, demonstrating that 2D histological sections may not be representative of their neighboring tissues. In sum, we demonstrate that 3D assessments are necessary to accurately assess tissue composition in normal and abnormal specimens and in order to accurately determine neoplastic content. These results emphasize the importance of intra-sample heterogeneity in tissue mapping efforts.

Power-law growth models explain incidences and sizes of pancreatic cancer precursor lesions and confirm spatial genomic findings.

Pancreatic ductal adenocarcinoma is a rare but lethal cancer. Recent evidence reveals that pancreatic intraepithelial neoplasms (PanINs), the microscopic precursor lesions in the pancreatic ducts that can give rise to invasive pancreatic cancer, are significantly larger and more prevalent than previously believed. Better understanding of the growth law dynamics of PanINs may improve our ability to understand how a miniscule fraction of these lesions makes the transition to invasive cancer. Here, using artificial intelligence (AI)-based three-dimensional (3D) tissue mapping method, we measured the volumes of >1,000 PanIN and found that lesion size is distributed according to a power law with a fitted exponent of -1.7 over > 3 orders of magnitude. Our data also suggest that PanIN growth is not very sensitive to the pancreatic microenvironment or an individual's age, family history, and lifestyle, and is rather shaped by general growth behavior. We analyze several models of PanIN growth and fit the predicted size distributions to the observed data. The best fitting models suggest that both intraductal spread of PanIN lesions and fusing of multiple lesions into large, highly branched structures drive PanIN growth patterns. This work lays the groundwork for future mathematical modeling efforts integrating PanIN incidence, morphology, genomic, and transcriptomic features to understand pancreas tumorigenesis, and demonstrates the utility of combining experimental measurement of human tissues with dynamic modeling for understanding cancer tumorigenesis.

Learning with limited target data to detect cells in cross-modality images.

Deep neural networks have achieved excellent cell or nucleus quantification performance in microscopy images, but they often suffer from performance degradation when applied to cross-modality imaging data. Unsupervised domain adaptation (UDA) based on generative adversarial networks (GANs) has recently improved the performance of cross-modality medical image quantification. However, current GAN-based UDA methods typically require abundant target data for model training, which is often very expensive or even impossible to obtain for real applications. In this paper, we study a more realistic yet challenging UDA situation, where (unlabeled) target training data is limited and previous work seldom delves into cell identification. We first enhance a dual GAN with task-specific modeling, which provides additional supervision signals to assist with generator learning. We explore both single-directional and bidirectional task-augmented GANs for domain adaptation. Then, we further improve the GAN by introducing a differentiable, stochastic data augmentation module to explicitly reduce discriminator overfitting. We examine source-, target-, and dual-domain data augmentation for GAN enhancement, as well as joint task and data augmentation in a unified GAN-based UDA framework. We evaluate the framework for cell detection on multiple public and in-house microscopy image datasets, which are acquired with different imaging modalities, staining protocols and/or tissue preparations. The experiments demonstrate that our method significantly boosts performance when compared with the reference baseline, and it is superior to or on par with fully supervised models that are trained with real target annotations. In addition, our method outperforms recent state-of-the-art UDA approaches by a large margin on different datasets.

Three-dimensional genomic mapping of human pancreatic tissue reveals striking multifocality and genetic heterogeneity in precancerous lesions.

Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic cancer and represents a critical opportunity for cancer interception. However, the number, size, shape, and connectivity of PanINs in human pancreatic tissue samples are largely unknown. In this study, we quantitatively assessed human PanINs using CODA, a novel machine-learning pipeline for 3D image analysis that generates quantifiable models of large pieces of human pancreas with single-cell resolution. Using a cohort of 38 large slabs of grossly normal human pancreas from surgical resection specimens, we identified striking multifocality of PanINs, with a mean burden of 13 spatially separate PanINs per cm3 of sampled tissue. Extrapolating this burden to the entire pancreas suggested a median of approximately 1000 PanINs in an entire pancreas. In order to better understand the clonal relationships within and between PanINs, we developed a pipeline for CODA-guided multi-region genomic analysis of PanINs, including targeted and whole exome sequencing. Multi-region assessment of 37 PanINs from eight additional human pancreatic tissue slabs revealed that almost all PanINs contained hotspot mutations in the oncogene KRAS, but no gene other than KRAS was altered in more than 20% of the analyzed PanINs. PanINs contained a mean of 13 somatic mutations per region when analyzed by whole exome sequencing. The majority of analyzed PanINs originated from independent clonal events, with distinct somatic mutation profiles between PanINs in the same tissue slab. A subset of the analyzed PanINs contained multiple KRAS mutations, suggesting a polyclonal origin even in PanINs that are contiguous by rigorous 3D assessment. This study leverages a novel 3D genomic mapping approach to describe, for the first time, the spatial and genetic multifocality of human PanINs, providing important insights into the initiation and progression of pancreatic neoplasia.

Cybersecurity and Information Assurance for the Clinical Laboratory.

BACKGROUND: Network-connected medical devices have rapidly proliferated in the wake of recent global catalysts, leaving clinical laboratories and healthcare organizations vulnerable to malicious actors seeking to ransom sensitive healthcare information. As organizations become increasingly dependent on integrated systems and data-driven patient care operations, a sudden cyberattack and the associated downtime can have a devastating impact on patient care and the institution as a whole. Cybersecurity, information security, and information assurance principles are, therefore, vital for clinical laboratories to fully prepare for what has now become inevitable, future cyberattacks. CONTENT: This review aims to provide a basic understanding of cybersecurity, information security, and information assurance principles as they relate to healthcare and the clinical laboratories. Common cybersecurity risks and threats are defined in addition to current proactive and reactive cybersecurity controls. Information assurance strategies are reviewed, including traditional castle-and-moat and zero-trust security models. Finally, ways in which clinical laboratories can prepare for an eventual cyberattack with extended downtime are discussed. SUMMARY: The future of healthcare is intimately tied to technology, interoperability, and data to deliver the highest quality of patient care. Understanding cybersecurity and information assurance is just the first preparative step for clinical laboratories as they ensure the protection of patient data and the continuity of their operations.

Low-Resource Adversarial Domain Adaptation for Cross-Modality Nucleus Detection.

Due to domain shifts, deep cell/nucleus detection models trained on one microscopy image dataset might not be applicable to other datasets acquired with different imaging modalities. Unsupervised domain adaptation (UDA) based on generative adversarial networks (GANs) has recently been exploited to close domain gaps and has achieved excellent nucleus detection performance. However, current GAN-based UDA model training often requires a large amount of unannotated target data, which may be prohibitively expensive to obtain in real practice. Additionally, these methods have significant performance degradation when using limited target training data. In this paper, we study a more realistic yet challenging UDA scenario, where (unannotated) target training data is very scarce, a low-resource case rarely explored for nucleus detection in previous work. Specifically, we augment a dual GAN network by leveraging a task-specific model to supplement the target-domain discriminator and facilitate generator learning with limited data. The task model is constrained by cross-domain prediction consistency to encourage semantic content preservation for image-to-image translation. Next, we incorporate a stochastic, differentiable data augmentation module into the task-augmented GAN network to further improve model training by alleviating discriminator overfitting. This data augmentation module is a plug-and-play component, requiring no modification of network architectures or loss functions. We evaluate the proposed low-resource UDA method for nucleus detection on multiple public cross-modality microscopy image datasets. With a single training image in the target domain, our method significantly outperforms recent state-of-the-art UDA approaches and delivers very competitive or superior performance over fully supervised models trained with real labeled target data.

CODA: quantitative 3D reconstruction of large tissues at cellular resolution.

A central challenge in biology is obtaining high-content, high-resolution information while analyzing tissue samples at volumes relevant to disease progression. We address this here with CODA, a method to reconstruct exceptionally large (up to multicentimeter cubed) tissues at subcellular resolution using serially sectioned hematoxylin and eosin-stained tissue sections. Here we demonstrate CODA's ability to reconstruct three-dimensional (3D) distinct microanatomical structures in pancreas, skin, lung and liver tissues. CODA allows creation of readily quantifiable tissue volumes amenable to biological research. As a testbed, we assess the microanatomy of the human pancreas during tumorigenesis within the branching pancreatic ductal system, labeling ten distinct structures to examine heterogeneity and structural transformation during neoplastic progression. We show that pancreatic precancerous lesions develop into distinct 3D morphological phenotypes and that pancreatic cancer tends to spread far from the bulk tumor along collagen fibers that are highly aligned to the 3D curves of ductal, lobular, vascular and neural structures. Thus, CODA establishes a means to transform broadly the structural study of human diseases through exploration of exhaustively labeled 3D microarchitecture.

Interactive Multimedia Reporting Technical Considerations: HIMSS-SIIM Collaborative White Paper.

Despite technological advances in the analysis of digital images for medical consultations, many health information systems lack the ability to correlate textual descriptions of image findings linked to the actual images. Images and reports often reside in separate silos in the medical record throughout the process of image viewing, report authoring, and report consumption. Forward-thinking centers and early adopters have created interactive reports with multimedia elements and embedded hyperlinks in reports that connect the narrative text with the related source images and measurements. Most of these solutions rely on proprietary single-vendor systems for viewing and reporting in the absence of any encompassing industry standards to facilitate interoperability with the electronic health record (EHR) and other systems. International standards have enabled the digitization of image acquisition, storage, viewing, and structured reporting. These provide the foundation to discuss enhanced reporting. Lessons learned in the digital transformation of radiology and pathology can serve as a basis for interactive multimedia reporting (IMR) across image-centric medical specialties. This paper describes the standard-based infrastructure and communications to fulfill recently defined clinical requirements through a consensus from an international workgroup of multidisciplinary medical specialists, informaticists, and industry participants. These efforts have led toward the development of an Integrating the Healthcare Enterprise (IHE) profile that will serve as a foundation for interoperable interactive multimedia reporting.

Trends in dermatology eponyms.

Background: Eponyms are ubiquitous in dermatology; however, their usage trends have not been studied. Objective: To characterize the usage of eponyms in dermatology from 1880 to 2020. Methods: Candidate eponyms were collected from a textbook and an online resource. A subset of these eponyms was deemed to be dermatology-focused by a panel of experienced dermatologists. Python scripts were used to permute eponyms into multiple variations and automatically search PubMed using BioPython's Entrez library. Results: The dermatologist panel designated 373 of 529 candidate eponyms as dermatology-focused. These eponyms were permuted into 3159 variations and searched in PubMed. The highest occurring dermatology-focused eponyms (DFEs) in the year 2020 included Leishmania, Behçet syndrome, Kaposi sarcoma, Langerhans cell histiocytosis, and Mohs surgery. Increased DFE usage in the general medical literature parallels the overall increase in the use of other eponyms in the medical literature. However, in the most cited dermatology journals, DFE usage did not increase in the past decade. There were several eponyms with decreased usage. Limitations: This study is limited to the publications in PubMed; only titles and abstracts could be queried. Conclusion: DFEs are increasing in usage in the general medical literature, but the usage of eponyms in the most cited dermatology journals has plateaued.

A Biopython-based method for comprehensively searching for eponyms in Pubmed.

Eponyms are common in medicine; however, their usage has varied between specialties and over time. A search of specific eponyms will reveal the frequency of usage within a medical specialty. While usage of eponyms can be studied by searching PubMed, manual searching can be time-consuming. As an alternative, we modified an existing Biopython method for searching PubMed. In this method, a list of disease eponyms is first manually collected in an Excel file. A Python script then creates permutations of the eponyms that might exist in the cited literature. These permutations include possessives (e.g., 's) as well as various forms of combining multiple surnames. PubMed is then automatically searched for this permutated library of eponyms, and duplicate citations are removed. The final output file may then be sorted and enumerated by all the data fields which exist in PubMed. This method will enable rapid searching and characterization of eponyms for any specialty of medicine. This method is agnostic to the type of terms searched and can be generally applied to the medical literature including non-eponymous terms such as gene names and chemical compounds.•Custom Python scripts using Biopython's Bio.Entrez module automate the search for medical eponyms.•This method can be more broadly used to search for any set of terms existing in PubMed.

Multispecialty Enterprise Imaging Workgroup Consensus on Interactive Multimedia Reporting Current State and Road to the Future: HIMSS-SIIM Collaborative White Paper.

Diagnostic and evidential static image, video clip, and sound multimedia are captured during routine clinical care in cardiology, dermatology, ophthalmology, pathology, physiatry, radiation oncology, radiology, endoscopic procedural specialties, and other medical disciplines. Providers typically describe the multimedia findings in contemporaneous electronic health record clinical notes or associate a textual interpretative report. Visual communication aids commonly used to connect, synthesize, and supplement multimedia and descriptive text outside medicine remain technically challenging to integrate into patient care. Such beneficial interactive elements may include hyperlinks between text, multimedia elements, alphanumeric and geometric annotations, tables, graphs, timelines, diagrams, anatomic maps, and hyperlinks to external educational references that patients or provider consumers may find valuable. This HIMSS-SIIM Enterprise Imaging Community workgroup white paper outlines the current and desired clinical future state of interactive multimedia reporting (IMR). The workgroup adopted a consensus definition of IMR as "interactive medical documentation that combines clinical images, videos, sound, imaging metadata, and/or image annotations with text, typographic emphases, tables, graphs, event timelines, anatomic maps, hyperlinks, and/or educational resources to optimize communication between medical professionals, and between medical professionals and their patients." This white paper also serves as a precursor for future efforts toward solving technical issues impeding routine interactive multimedia report creation and ingestion into electronic health records.

Artificial intelligence for automating the measurement of histologic image biomarkers.

Artificial intelligence has been applied to histopathology for decades, but the recent increase in interest is attributable to well-publicized successes in the application of deep-learning techniques, such as convolutional neural networks, for image analysis. Recently, generative adversarial networks (GANs) have provided a method for performing image-to-image translation tasks on histopathology images, including image segmentation. In this issue of the JCI, Koyuncu et al. applied GANs to whole-slide images of p16-positive oropharyngeal squamous cell carcinoma (OPSCC) to automate the calculation of a multinucleation index (MuNI) for prognostication in p16-positive OPSCC. Multivariable analysis showed that the MuNI was prognostic for disease-free survival, overall survival, and metastasis-free survival. These results are promising, as they present a prognostic method for p16-positive OPSCC and highlight methods for using deep learning to measure image biomarkers from histopathologic samples in an inherently explainable manner.

Eponyms in clinical chemistry.

BACKGROUND: Eponyms are commonly used in medicine, but there are no specific studies of the use of eponyms in clinical chemistry. METHODS: Clinical chemistry eponyms were manually collected from books, review articles and journal articles from 1847 through 2020. Eponym usage was examined by searching titles and abstracts in PubMed. Custom Python scripts were used to first permute eponyms into multiple forms, and then to search PubMed using Biopython. The eponyms identified in PubMed were further focused on 2 clinical chemistry journals Clinica Chimica Acta [CCA] and Clinical Chemistry [CCJ]. RESULTS: The manual collection identified >300 eponyms in clinical chemistry. The Biopython search of PubMed identified a subset of 97 unique eponyms in 33,232 articles. PubMed identified 26 eponyms used in 130 CCA articles; whereas a full-text search identified 1187 articles. In comparison, PubMed identified 36 eponyms used in 158 CCJ articles; whereas a full-text CCJ search identified 708 articles. PubMed shows that the journals CCA and CCJ had a peak number of eponym citations in 1977 followed by a steady decline. CONCLUSIONS: Eponyms have been frequently used in clinical chemistry with 97 eponyms in common use in PubMed. Overall, the use of clinical chemistry eponyms appears to be declining.

Bidirectional Mapping-Based Domain Adaptation for Nucleus Detection in Cross-Modality Microscopy Images.

Cell or nucleus detection is a fundamental task in microscopy image analysis and has recently achieved state-of-the-art performance by using deep neural networks. However, training supervised deep models such as convolutional neural networks (CNNs) usually requires sufficient annotated image data, which is prohibitively expensive or unavailable in some applications. Additionally, when applying a CNN to new datasets, it is common to annotate individual cells/nuclei in those target datasets for model re-learning, leading to inefficient and low-throughput image analysis. To tackle these problems, we present a bidirectional, adversarial domain adaptation method for nucleus detection on cross-modality microscopy image data. Specifically, the method learns a deep regression model for individual nucleus detection with both source-to-target and target-to-source image translation. In addition, we explicitly extend this unsupervised domain adaptation method to a semi-supervised learning situation and further boost the nucleus detection performance. We evaluate the proposed method on three cross-modality microscopy image datasets, which cover a wide variety of microscopy imaging protocols or modalities, and obtain a significant improvement in nucleus detection compared to reference baseline approaches. In addition, our semi-supervised method is very competitive with recent fully supervised learning models trained with all real target training labels.

Display Characteristics and Their Impact on Digital Pathology: A Current Review of Pathologists' Future "Microscope".

Digital displays (monitors) are an indispensable component of a pathologists' daily workflow, from writing reports, viewing whole-slide images, or browsing the Internet. Due to a paucity of literature and experience surrounding display use and standardization in pathology, the Food and Drug Administration's (FDA) has currently restricted FDA-cleared whole-slide imaging systems to a specific model of display for each system, which at this time consists of only medical-grade (MG) displays. Further, given that a pathologists' display will essentially become their new surrogate "microscope," it becomes exceedingly important that all pathologists have a basic understanding of fundamental display properties and their functional consequences. This review seeks to: (a) define and summarize the current and emerging display technology, terminology, features, and regulation as they pertain to pathologists and review the current literature on the impact of different display types (e.g. MG vs. consumer off the shelf vs. professional grade) on pathologists' diagnostic performance and (b) discuss the impact of the recent digital pathology device componentization and the coronavirus disease 2019 public emergency on the pixel pathway and display use for remote digital pathology. Display technology has changed dramatically over the past 20 years and continues to change at a rapid rate. There is a paucity of published studies to date that investigate how display type affects pathologist performance, with more research necessary in order to develop standards and minimum specifications for displays in digital pathology. Given the complexity of modern displays, pathologists must become better informed regarding display technology if they wish to have more choice over their future "microscopes."