The slow-paced digital evolution of pathology: lights and shadows from a multifaceted board.

Objective: The digital revolution in pathology represents an invaluable resource fto optimise costs, reduce the risk of error and improve patient care, even though it is still adopted in a minority of laboratories. Barriers include concerns about initial costs, lack of confidence in using whole slide images for primary diagnosis, and lack of guidance on transition. To address these challenges and develop a programme to facilitate the introduction of digital pathology (DP) in Italian pathology departments, a panel discussion was set up to identify the key points to be considered. Methods: On 21 July 2022, an initial conference call was held on Zoom to identify the main issues to be discussed during the face-to-face meeting. The final summit was divided into four different sessions: (I) the definition of DP, (II) practical applications of DP, (III) the use of AI in DP, (IV) DP and education. Results: Essential requirements for the implementation of DP are a fully tracked and automated workflow, selection of the appropriate scanner based on the specific needs of each department, and a strong commitment combined with coordinated teamwork (pathologists, technicians, biologists, IT service and industries). This could reduce human error, leading to the application of AI tools for diagnosis, prognosis and prediction. Open challenges are the lack of specific regulations for virtual slide storage and the optimal storage solution for large volumes of slides. Conclusion: Teamwork is key to DP transition, including close collaboration with industry. This will ease the transition and help bridge the gap that currently exists between many labs and full digitisation. The ultimate goal is to improve patient care.

Natural Language Processing to extract SNOMED-CT codes from pathological reports.

Objective: The use of standardized structured reports (SSR) and suitable terminologies like SNOMED-CT can enhance data retrieval and analysis, fostering large-scale studies and collaboration. However, the still large prevalence of narrative reports in our laboratories warrants alternative and automated labeling approaches. In this project, natural language processing (NLP) methods were used to associate SNOMED-CT codes to structured and unstructured reports from an Italian Digital Pathology Department. Methods: Two NLP-based automatic coding systems (support vector machine, SVM, and long-short term memory, LSTM) were trained and applied to a series of narrative reports. Results: The 1163 cases were tested with both algorithms, showing good performances in terms of accuracy, precision, recall, and F1 score, with SVM showing slightly better performances as compared to LSTM (0.84, 0.87, 0.83, 0.82 vs 0.83, 0.85, 0.83, 0.82, respectively). The integration of an explainability allowed identification of terms and groups of words of importance, enabling fine-tuning, balancing semantic meaning and model performance. Conclusions: AI tools allow the automatic SNOMED-CT labeling of the pathology archives, providing a retrospective fix to the large lack of organization of narrative reports.

Marker controlled superpixel nuclei segmentation and automatic counting on immunohistochemistry staining images.

MOTIVATION: For the diagnosis of cancer, manually counting nuclei on massive histopathological images is tedious and the counting results might vary due to the subjective nature of the operation. RESULTS: This paper presents a new segmentation and counting method for nuclei, which can automatically provide nucleus counting results. This method segments nuclei with detected nuclei seed markers through a modified simple one-pass superpixel segmentation method. Rather than using a single pixel as a seed, we created a superseed for each nucleus to involve more information for improved segmentation results. Nucleus pixels are extracted by a newly proposed fusing method to reduce stain variations and preserve nucleus contour information. By evaluating segmentation results, the proposed method was compared to five existing methods on a dataset with 52 immunohistochemically (IHC) stained images. Our proposed method produced the highest mean F1-score of 0.668. By evaluating the counting results, another dataset with more than 30 000 IHC stained nuclei in 88 images were prepared. The correlation between automatically generated nucleus counting results and manual nucleus counting results was up to R2 = 0.901 (P < 0.001). By evaluating segmentation results of proposed method-based tool, we tested on a 2018 Data Science Bowl (DSB) competition dataset, three users obtained DSB score of 0.331 ± 0.006. AVAILABILITY AND IMPLEMENTATION: The proposed method has been implemented as a plugin tool in ImageJ and the source code can be freely downloaded. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Ontological modeling of the International Classification of Functioning, Disabilities and Health (ICF): Activities&Participation and Environmental Factors components.

BACKGROUND: The International Classification of Functioning, Disability and Health (ICF) is a classification of health and health-related states developed by the World Health Organization (WHO) to provide a standard and unified language to be used as a reference model for the description of health and health-related states. The concept of functioning on which ICF is based is that of a "dynamic interaction between a person's health condition, environmental factors and personal factors". This overall model has been translated into a classification covering all the main components of functioning. However, the practical use of ICF has highlighted some formal problems, mainly concerning conceptual clarity and ontological coherence. METHODS: In the present work, we propose an initial ontological formalization of ICF beyond its current status, focusing specifically on the interaction between activities and participation and environmental factors. The formalization has been based on ontology engineering methods to drive goal and scope definition, knowledge acquisition, selection of an upper ontology for mapping, conceptual model definition and evaluation, and finally representation using the Ontology Web Language (OWL). RESULTS: A conceptual model has been defined in a graphical language that included 202 entities, when possible mapped to the SUMO upper ontology. The conceptual model has been validated against 60 case studies from the literature, plus 6 ad-hoc case studies. The model has been then represented using OWL. CONCLUSIONS: This formalization might provide the basis for a revision of the ICF classification in line with current efforts made by WHO on the International Classification of Diseases and on the International Classification of Health Interventions.

Biomarkers of lymphoma in Sjögren's syndrome and evaluation of the lymphoma risk in prelymphomatous conditions: results of a multicenter study.

OBJECTIVES: To define the biomarkers associated with lymphoproliferation in primary Sjögren's syndrome (pSS) by distinguishing in separate groups the two best-recognized non-malignant prelymphomatous conditions in pSS, i.e., salivary gland swelling and cryoglobulinemic vasculitis (CV). METHODS: A multicenter study was conducted in 5 centres. Patients fulfilled the following criteria: (1) positive AECG criteria for pSS, (2) serum cryoglobulins evaluated, and (3) lack of hepatitis C virus infection. Four groups were distinguished and analysed by multinomial analyses: (1) B-cell non-Hodgkin's lymphoma (NHL), (2) CV without lymphoma, (3) salivary swelling without NHL (SW), and (4) pSS patients without NHL or prelymphomatous conditions. RESULTS: Six hundred and sixty-one patients were studied. Group 1/NHL comprised 40/661 (6.1%) patients, Group 2/CV 17/661 (2.6%), Group 3/SW 180/661 (27.2%), and Group 4/pSS controls 424/661 (64.1%). Low C4 [relative-risk ratio (RRR) 8.3], cryoglobulins (RRR 6.8), anti-La antibodies (RRR 5.2), and leukopenia (RRR 3.3) were the variables distinguishing Group 1/NHL from Group 4/Controls. As concerns the subset of patients with prelymphomatous conditions, the absence of these biomarkers provided a negative predictive value for lymphoma of 98% in patients with salivary swelling (Group 3/SW). Additional follow-up studies in patients with SW confirmed the high risk of lymphoma when at least 2/4 biomarkers were positive. CONCLUSIONS: Lymphoma-associated biomarkers were defined in a multicentre series of well-characterized patients with pSS, by dissecting the cohort in the pSS-associated prelymphomatous conditions. Notably, it was demonstrated for the first time that among the pSS patients with salivary swelling, only those with positive biomarkers present an increased risk of lymphoma evolution.

Optimizing Vision Transformers for Histopathology: Pretraining and Normalization in Breast Cancer Classification.

This paper introduces a self-attention Vision Transformer model specifically developed for classifying breast cancer in histology images. We examine various training strategies and configurations, including pretraining, dimension resizing, data augmentation and color normalization strategies, patch overlap, and patch size configurations, in order to evaluate their impact on the effectiveness of the histology image classification. Additionally, we provide evidence for the increase in effectiveness gathered through geometric and color data augmentation techniques. We primarily utilize the BACH dataset to train and validate our methods and models, but we also test them on two additional datasets, BRACS and AIDPATH, to verify their generalization capabilities. Our model, developed from a transformer pretrained on ImageNet, achieves an accuracy rate of 0.91 on the BACH dataset, 0.74 on the BRACS dataset, and 0.92 on the AIDPATH dataset. Using a model based on the prostate small and prostate medium HistoEncoder models, we achieve accuracy rates of 0.89 and 0.86, respectively. Our results suggest that pretraining on large-scale general datasets like ImageNet is advantageous. We also show the potential benefits of using domain-specific pretraining datasets, such as extensive histopathological image collections as in HistoEncoder, though not yet with clear advantages.

Enhancing AI Research for Breast Cancer: A Comprehensive Review of Tumor-Infiltrating Lymphocyte Datasets.

The field of immunology is fundamental to our understanding of the intricate dynamics of the tumor microenvironment. In particular, tumor-infiltrating lymphocyte (TIL) assessment emerges as essential aspect in breast cancer cases. To gain comprehensive insights, the quantification of TILs through computer-assisted pathology (CAP) tools has become a prominent approach, employing advanced artificial intelligence models based on deep learning techniques. The successful recognition of TILs requires the models to be trained, a process that demands access to annotated datasets. Unfortunately, this task is hampered not only by the scarcity of such datasets, but also by the time-consuming nature of the annotation phase required to create them. Our review endeavors to examine publicly accessible datasets pertaining to the TIL domain and thereby become a valuable resource for the TIL community. The overall aim of the present review is thus to make it easier to train and validate current and upcoming CAP tools for TIL assessment by inspecting and evaluating existing publicly available online datasets.

Supporting Fair and Efficient Emergency Medical Services in a Large Heterogeneous Region.

Emergency Medical Services (EMS) are crucial in delivering timely and effective medical care to patients in need. However, the complex and dynamic nature of operations poses challenges for decision-making processes at strategic, tactical, and operational levels. This paper proposes an action-driven strategy for EMS management, employing a multi-objective optimizer and a simulator to evaluate potential outcomes of decisions. The approach combines historical data with dynamic simulations and multi-objective optimization techniques to inform decision-makers and improve the overall performance of the system. The research focuses on the Friuli Venezia Giulia region in north-eastern Italy. The region encompasses various landscapes and demographic situations that challenge fairness and equity in service access. Similar challenges are faced in other regions with comparable characteristics. The Decision Support System developed in this work accurately models the real-world system and provides valuable feedback and suggestions to EMS professionals, enabling them to make informed decisions and enhance the efficiency and fairness of the system.

Automated ICF Coding of Rehabilitation Notes for Low-Resource Languages via Continual Training of Language Models.

The coding of medical documents and in particular of rehabilitation notes using the International Classification of Functioning, Disability and Health (ICF) is a difficult task showing low agreement among experts. Such difficulty is mainly caused by the specific terminology that needs to be used for the task. In this paper, we address the task developing a model based on a large language model, BERT. By leveraging continual training of such a model using ICF textual descriptions, we are able to effectively encode rehabilitation notes expressed in Italian, an under-resourced language.

Harmonization of ICF Body Structures and ICD-11 Anatomic Detail: One foundation for multiple classifications.

The Family of International Classifications of the World Health Organization (WHO-FIC) currently includes three reference classifications, namely International Classification of Diseases (ICD), International Classification of Functioning, Disability, and Health (ICF), and International Classification of Health Interventions (ICHI). Recently, the three classifications have been incorporated into a single WHO-FIC Foundation that serves as the repository of all concepts in the classifications. Each classification serves a specific classification need. However, they share some common concepts that are present, in different forms, in two or all of them. For the WHO-FIC Foundation to be a logically consistent repository without duplicates, these common concepts must be reconciled. One important set of shared concepts is the representation of human anatomy entities, which are not always modeled in the same way and with the same level of detail. To understand the relationships among the three anatomical representations, an effort is needed to compare them, identifying common areas, gaps, and compatible and incompatible modeling. The work presented here contributes to this effort, focusing on the anatomy representations in ICF and ICD-11. For this aim, three experts were asked to identify, for each entity in the ICF Body Structures, one or more entities in the ICD-11 Anatomic Detail that could be considered identical, broader or narrower. To do this, they used a specifically developed web application, which also automatically identified the most obvious equivalences. A total of 631 maps were independently identified by the three mappers for 218 ICF Body Structures, with an interobserver agreement of 93.5%. Together with 113 maps identified by the software, they were then consolidated into 434 relations. The results highlight some differences between the two classifications: in general, ICF is less detailed than ICD-11; ICF favors lumping of structures; in very few cases, the two classifications follow different anatomic models. For these issues, solutions have to be found that are compliant with the WHO approach to classification modeling and maintenance.

Digital pathology world tour.

Objective: Digital pathology (DP) is currently in the spotlight and is rapidly gaining ground, even though the history of this field spans decades. Despite great technological progress, the adoption of DP for routine clinical diagnostic use remains limited. Methods: A systematic search was conducted in the electronic databases Pubmed-MEDLINE and Embase. Inclusion criteria were all published studies that encompassed any application of DP. Results: Of 4888 articles retrieved, 4041 were included. Relevant articles were categorized as "diagnostic" (147/4041, 4%) where DP was utilized for routine diagnostic workflow and "non-diagnostic" (3894/4041, 96%) for all other applications. The "non-diagnostic" articles were further categorized according to DP application including "artificial intelligence" (33%), "education" (5%), "narrative" (17%) for reviews and editorials, and "technical" (45%) for pure research publications. Conclusion: This manuscript provided temporal and geographical insight into the global adoption of DP by analyzing the published scientific literature.

ICF machine: a web-based system for collection of ICF data.

The International Classification of Functioning, Disability and Health (ICF) is a WHO classification for health and health-related issues. In order to foster ICF application in information systems, we devised an implementation profile in ClaML (Classification Markup Language) that allows for representation of ICF subsets and we developed a web-based system for collecting ICF data based on from their ClaML representation. The implementation profile and the application have been tested on 17 subsets, which have been translated into ClaML and then submitted to the web application, to produce test documents.

A smartphone application for preventing exercise-induced glycemic imbalances in type 1 diabetic patients.

Regular moderate-intensity physical activity is strongly recommended as well in patients with type 1 diabetes mellitus. However, the more frequent complication of exercise in T1DM patients is an excessive fall of glycaemia, which remains thus the strongest barrier to physical activity and the number of difficulties patients have to meet often further discourage them. Recently, a new algorithm has been proposed, that estimates, on a patient- and situation-specific basis, the amount of supplemental carbohydrates required by diabetic patients in order to exercise under safe blood glucose levels. The present paper discusses an implementation of the ECRES algorithm aimed at smartphones, and its preliminary evaluation from the accuracy point of view versus the original implementation, as well as usability. The developed mobile application replicates the original algorithm in a portable device that, after its preliminary experimentation, may be useful to make physical activity easier for diabetic patients.

Standards and specifications in pathology: image management, report management and terminology.

For making medical decisions, healthcare professionals require that all necessary information is both correct and easily available. Collaborative Digital Anatomic Pathology refers to the use of information technology that supports the creation and sharing or exchange of information, including data and images, during the complex workflow performed in an Anatomic Pathology department from specimen reception to report transmission and exploitation. Collaborative Digital Anatomic Pathology is supported by standardization efforts toward knowledge representation for sharable and computable clinical information. The goal of the international integrating the Healthcare Enterprise (IHE) initiative is precisely specifying how medical informatics standards should be implemented to meet specific health care needs and making systems integration more efficient and less expensive. The IHE Anatomic Pathology initiative was launched to implement the best use of medical informatics standards in order to produce, share and exchange machine-readable structured reports and their evidences (including whole slide images) within hospitals and across healthcare facilities. DICOM supplements 122 and 145 provide flexible object information definitions dedicated respectively to specimen description and WSI acquisition, storage and display. The profiles "Anatomic Pathology Reporting for Public Health" (ARPH) and "Anatomic Pathology Structured Report" (APSR) provide standard templates and transactions for sharing or exchanging structured reports in which textual observations - encoded using PathLex, an international controlled vocabulary currently being mapped to SNOMED CT concepts - may be bound to digital images or regions of interest in images. Current implementations of IHE Anatomic Pathology profiles in North America, France and Spain demonstrate the applicability of recent advances in standards for Collaborative Digital Anatomic Pathology. The use of machine-readable format of Anatomic Pathology information supports the development of computer-based decision support as well as secondary use of Anatomic Pathology information for research or public health.

Preliminary Validation of a Rule-Based System for Mortality Coding Using ICD-11.

A crucial process for world-level mortality statistics is the capability to identify the underlying cause of death from death certificates. Currently such certificates are coded using ICD-10. The selection of the underlying cause is done by means of semi-automated rule-based systems. However, starting from 2022, countries should begin to adopt ICD-11, for which no system is already available. The present paper describes the architecture of a novel system for automated UC selection, with classification-independent rules, and its preliminary validation on two sets of death certificates coded with ICD-10 and ICD-11.

HEROHE Challenge: Predicting HER2 Status in Breast Cancer from Hematoxylin-Eosin Whole-Slide Imaging.

Breast cancer is the most common malignancy in women worldwide, and is responsible for more than half a million deaths each year. The appropriate therapy depends on the evaluation of the expression of various biomarkers, such as the human epidermal growth factor receptor 2 (HER2) transmembrane protein, through specialized techniques, such as immunohistochemistry or in situ hybridization. In this work, we present the HER2 on hematoxylin and eosin (HEROHE) challenge, a parallel event of the 16th European Congress on Digital Pathology, which aimed to predict the HER2 status in breast cancer based only on hematoxylin-eosin-stained tissue samples, thus avoiding specialized techniques. The challenge consisted of a large, annotated, whole-slide images dataset (509), specifically collected for the challenge. Models for predicting HER2 status were presented by 21 teams worldwide. The best-performing models are presented by detailing the network architectures and key parameters. Methods are compared and approaches, core methodologies, and software choices contrasted. Different evaluation metrics are discussed, as well as the performance of the presented models for each of these metrics. Potential differences in ranking that would result from different choices of evaluation metrics highlight the need for careful consideration at the time of their selection, as the results show that some metrics may misrepresent the true potential of a model to solve the problem for which it was developed. The HEROHE dataset remains publicly available to promote advances in the field of computational pathology.

Best Practice Recommendations for the Implementation of a Digital Pathology Workflow in the Anatomic Pathology Laboratory by the European Society of Digital and Integrative Pathology (ESDIP).

The interest in implementing digital pathology (DP) workflows to obtain whole slide image (WSI) files for diagnostic purposes has increased in the last few years. The increasing performance of technical components and the Food and Drug Administration (FDA) approval of systems for primary diagnosis led to increased interest in applying DP workflows. However, despite this revolutionary transition, real world data suggest that a fully digital approach to the histological workflow has been implemented in only a minority of pathology laboratories. The objective of this study is to facilitate the implementation of DP workflows in pathology laboratories, helping those involved in this process of transformation to identify: (a) the scope and the boundaries of the DP transformation; (b) how to introduce automation to reduce errors; (c) how to introduce appropriate quality control to guarantee the safety of the process and (d) the hardware and software needed to implement DP systems inside the pathology laboratory. The European Society of Digital and Integrative Pathology (ESDIP) provided consensus-based recommendations developed through discussion among members of the Scientific Committee. The recommendations are thus based on the expertise of the panel members and on the agreement obtained after virtual meetings. Prior to publication, the recommendations were reviewed by members of the ESDIP Board. The recommendations comprehensively cover every step of the implementation of the digital workflow in the anatomic pathology department, emphasizing the importance of interoperability, automation and tracking of the entire process before the introduction of a scanning facility. Compared to the available national and international guidelines, the present document represents a practical, handy reference for the correct implementation of the digital workflow in Europe.

Classification of Histologic Images Using a Single Staining: Experiments with Deep Learning on Deconvolved Images.

The automated analysis of digitized immunohistochemistry microscope slides is usually a challenging task, because markers should be analysed on the tumor area only. Tumor areas could be recognized on a different slide, stained with Haematoxylin-Eosin. The basic idea of the present poster is to evaluate how well deep learning methods perform on the single haematoxylin component of staining, with the prospective possibility of developing a classifier able to recognize tumor areas on IHC slides on their haematoxylin component only. In a preliminary experiment, single stain images obtained by H-E color deconvolution showed an accuracy of 0.808 and 0.812 for Hematoxilyn and Eosin components, respectively.

Detection of HER2 from Haematoxylin-Eosin Slides Through a Cascade of Deep Learning Classifiers via Multi-Instance Learning.

Breast cancer is the most frequently diagnosed cancer in woman. The correct identification of the HER2 receptor is a matter of major importance when dealing with breast cancer: an over-expression of HER2 is associated with aggressive clinical behaviour; moreover, HER2 targeted therapy results in a significant improvement in the overall survival rate. In this work, we employ a pipeline based on a cascade of deep neural network classifiers and multi-instance learning to detect the presence of HER2 from Haematoxylin-Eosin slides, which partly mimics the pathologist's behaviour by first recognizing cancer and then evaluating HER2. Our results show that the proposed system presents a good overall effectiveness. Furthermore, the system design is prone to further improvements that can be easily deployed in order to increase the effectiveness score.