Daily Papers

Pathology plays a critical role in diagnosing a wide range of diseases, yet existing approaches often rely heavily on task-specific models trained on extensive, well-labeled datasets. These methods face sustainability challenges due to the diversity of pathologies and the labor-intensive nature of data collection. To address these limitations, we highlight the need for universal multimodal embeddings that can support multiple downstream tasks. Previous approaches often involve fine-tuning CLIP-based models, which handle images and text separately, limiting their ability to capture complex multimodal relationships. Additionally, these models are evaluated across diverse datasets without a unified benchmark for assessing multimodal embeddings in pathology. To address these challenges, we propose MLLM4PUE, a novel framework that leverages Multimodal Large Language Models (MLLMs) to generate Pathology Universal Embeddings. The MLLM4PUE framework not only facilitates robust integration of images and text but also enhances understanding and fusion capabilities across various tasks. We further introduce the Pathology Multimodal Embedding Benchmark (PMEB), a comprehensive benchmark designed to assess the quality of pathology multimodal embeddings. PMEB comprises 15 original tasks drawn from 14 datasets, organized into three meta-tasks: retrieval, classification, and composed retrieval. Experimental results demonstrate the superiority of MLLM4PUE, illustrating MLLM-based models can effectively support a wide range of downstream tasks and unify the research direction for foundation models in pathology.

Deep learning models have shown promise in histopathology image analysis, but their opaque decision-making process poses challenges in high-risk medical scenarios. Here we introduce HIPPO, an explainable AI method that interrogates attention-based multiple instance learning (ABMIL) models in computational pathology by generating counterfactual examples through tissue patch modifications in whole slide images. Applying HIPPO to ABMIL models trained to detect breast cancer metastasis reveals that they may overlook small tumors and can be misled by non-tumor tissue, while attention mapsx2014widely used for interpretationx2014often highlight regions that do not directly influence predictions. By interpreting ABMIL models trained on a prognostic prediction task, HIPPO identified tissue areas with stronger prognostic effects than high-attention regions, which sometimes showed counterintuitive influences on risk scores. These findings demonstrate HIPPO's capacity for comprehensive model evaluation, bias detection, and quantitative hypothesis testing. HIPPO greatly expands the capabilities of explainable AI tools to assess the trustworthy and reliable development, deployment, and regulation of weakly-supervised models in computational pathology.

The accelerated adoption of digital pathology and advances in deep learning have enabled the development of powerful models for various pathology tasks across a diverse array of diseases and patient cohorts. However, model training is often difficult due to label scarcity in the medical domain and the model's usage is limited by the specific task and disease for which it is trained. Additionally, most models in histopathology leverage only image data, a stark contrast to how humans teach each other and reason about histopathologic entities. We introduce CONtrastive learning from Captions for Histopathology (CONCH), a visual-language foundation model developed using diverse sources of histopathology images, biomedical text, and notably over 1.17 million image-caption pairs via task-agnostic pretraining. Evaluated on a suite of 13 diverse benchmarks, CONCH can be transferred to a wide range of downstream tasks involving either or both histopathology images and text, achieving state-of-the-art performance on histology image classification, segmentation, captioning, text-to-image and image-to-text retrieval. CONCH represents a substantial leap over concurrent visual-language pretrained systems for histopathology, with the potential to directly facilitate a wide array of machine learning-based workflows requiring minimal or no further supervised fine-tuning.

Representation learning of pathology whole-slide images (WSIs) has been has primarily relied on weak supervision with Multiple Instance Learning (MIL). However, the slide representations resulting from this approach are highly tailored to specific clinical tasks, which limits their expressivity and generalization, particularly in scenarios with limited data. Instead, we hypothesize that morphological redundancy in tissue can be leveraged to build a task-agnostic slide representation in an unsupervised fashion. To this end, we introduce PANTHER, a prototype-based approach rooted in the Gaussian mixture model that summarizes the set of WSI patches into a much smaller set of morphological prototypes. Specifically, each patch is assumed to have been generated from a mixture distribution, where each mixture component represents a morphological exemplar. Utilizing the estimated mixture parameters, we then construct a compact slide representation that can be readily used for a wide range of downstream tasks. By performing an extensive evaluation of PANTHER on subtyping and survival tasks using 13 datasets, we show that 1) PANTHER outperforms or is on par with supervised MIL baselines and 2) the analysis of morphological prototypes brings new qualitative and quantitative insights into model interpretability.

Tissue phenotyping is a fundamental computational pathology (CPath) task in learning objective characterizations of histopathologic biomarkers in anatomic pathology. However, whole-slide imaging (WSI) poses a complex computer vision problem in which the large-scale image resolutions of WSIs and the enormous diversity of morphological phenotypes preclude large-scale data annotation. Current efforts have proposed using pretrained image encoders with either transfer learning from natural image datasets or self-supervised pretraining on publicly-available histopathology datasets, but have not been extensively developed and evaluated across diverse tissue types at scale. We introduce UNI, a general-purpose self-supervised model for pathology, pretrained using over 100 million tissue patches from over 100,000 diagnostic haematoxylin and eosin-stained WSIs across 20 major tissue types, and evaluated on 33 representative CPath clinical tasks in CPath of varying diagnostic difficulties. In addition to outperforming previous state-of-the-art models, we demonstrate new modeling capabilities in CPath such as resolution-agnostic tissue classification, slide classification using few-shot class prototypes, and disease subtyping generalization in classifying up to 108 cancer types in the OncoTree code classification system. UNI advances unsupervised representation learning at scale in CPath in terms of both pretraining data and downstream evaluation, enabling data-efficient AI models that can generalize and transfer to a gamut of diagnostically-challenging tasks and clinical workflows in anatomic pathology.

Recent advancements in Digital Pathology (DP), particularly through artificial intelligence and Foundation Models, have underscored the importance of large-scale, diverse, and richly annotated datasets. Despite their critical role, publicly available Whole Slide Image (WSI) datasets often lack sufficient scale, tissue diversity, and comprehensive clinical metadata, limiting the robustness and generalizability of AI models. In response, we introduce the HISTAI dataset, a large, multimodal, open-access WSI collection comprising over 60,000 slides from various tissue types. Each case in the HISTAI dataset is accompanied by extensive clinical metadata, including diagnosis, demographic information, detailed pathological annotations, and standardized diagnostic coding. The dataset aims to fill gaps identified in existing resources, promoting innovation, reproducibility, and the development of clinically relevant computational pathology solutions. The dataset can be accessed at https://github.com/HistAI/HISTAI.

Multiple Instance Learning (MIL) has emerged as a dominant paradigm to extract discriminative feature representations within Whole Slide Images (WSIs) in computational pathology. Despite driving notable progress, existing MIL approaches suffer from limitations in facilitating comprehensive and efficient interactions among instances, as well as challenges related to time-consuming computations and overfitting. In this paper, we incorporate the Selective Scan Space State Sequential Model (Mamba) in Multiple Instance Learning (MIL) for long sequence modeling with linear complexity, termed as MambaMIL. By inheriting the capability of vanilla Mamba, MambaMIL demonstrates the ability to comprehensively understand and perceive long sequences of instances. Furthermore, we propose the Sequence Reordering Mamba (SR-Mamba) aware of the order and distribution of instances, which exploits the inherent valuable information embedded within the long sequences. With the SR-Mamba as the core component, MambaMIL can effectively capture more discriminative features and mitigate the challenges associated with overfitting and high computational overhead. Extensive experiments on two public challenging tasks across nine diverse datasets demonstrate that our proposed framework performs favorably against state-of-the-art MIL methods. The code is released at https://github.com/isyangshu/MambaMIL.

Computational pathology can lead to saving human lives, but models are annotation hungry and pathology images are notoriously expensive to annotate. Self-supervised learning has shown to be an effective method for utilizing unlabeled data, and its application to pathology could greatly benefit its downstream tasks. Yet, there are no principled studies that compare SSL methods and discuss how to adapt them for pathology. To address this need, we execute the largest-scale study of SSL pre-training on pathology image data, to date. Our study is conducted using 4 representative SSL methods on diverse downstream tasks. We establish that large-scale domain-aligned pre-training in pathology consistently out-performs ImageNet pre-training in standard SSL settings such as linear and fine-tuning evaluations, as well as in low-label regimes. Moreover, we propose a set of domain-specific techniques that we experimentally show leads to a performance boost. Lastly, for the first time, we apply SSL to the challenging task of nuclei instance segmentation and show large and consistent performance improvements under diverse settings.

Advancing AI in computational pathology requires large, high-quality, and diverse datasets, yet existing public datasets are often limited in organ diversity, class coverage, or annotation quality. To bridge this gap, we introduce SPIDER (Supervised Pathology Image-DEscription Repository), the largest publicly available patch-level dataset covering multiple organ types, including Skin, Colorectal, and Thorax, with comprehensive class coverage for each organ. SPIDER provides high-quality annotations verified by expert pathologists and includes surrounding context patches, which enhance classification performance by providing spatial context. Alongside the dataset, we present baseline models trained on SPIDER using the Hibou-L foundation model as a feature extractor combined with an attention-based classification head. The models achieve state-of-the-art performance across multiple tissue categories and serve as strong benchmarks for future digital pathology research. Beyond patch classification, the model enables rapid identification of significant areas, quantitative tissue metrics, and establishes a foundation for multimodal approaches. Both the dataset and trained models are publicly available to advance research, reproducibility, and AI-driven pathology development. Access them at: https://github.com/HistAI/SPIDER

The field of computational pathology has recently seen rapid advances driven by the development of modern vision foundation models (FMs), typically trained on vast collections of pathology images. Recent studies demonstrate that increasing the training data set and model size and integrating domain-specific image processing techniques can significantly enhance the model's performance on downstream tasks. Building on these insights, our work incorporates several recent modifications to the standard DINOv2 framework from the literature to optimize the training of pathology FMs. We also apply a post-training procedure for fine-tuning models on higher-resolution images to further enrich the information encoded in the embeddings. We present three novel pathology FMs trained on up to two orders of magnitude fewer WSIs than those used to train other state-of-the-art FMs while demonstrating a comparable or superior performance on downstream tasks. Even the model trained on TCGA alone (12k WSIs) outperforms most existing FMs and, on average, matches Virchow2, the second-best FM published to date. This suggests that there still remains a significant potential for further improving the models and algorithms used to train pathology FMs to take full advantage of the vast data collections.

Foundation models are reshaping computational pathology by enabling transfer learning, where models pre-trained on vast datasets can be adapted for downstream diagnostic, prognostic, and therapeutic response tasks. Despite these advances, foundation models are still limited in their ability to encode the entire gigapixel whole-slide images without additional training and often lack complementary multimodal data. Here, we introduce Threads, a slide-level foundation model capable of generating universal representations of whole-slide images of any size. Threads was pre-trained using a multimodal learning approach on a diverse cohort of 47,171 hematoxylin and eosin (H&E)-stained tissue sections, paired with corresponding genomic and transcriptomic profiles - the largest such paired dataset to be used for foundation model development to date. This unique training paradigm enables Threads to capture the tissue's underlying molecular composition, yielding powerful representations applicable to a wide array of downstream tasks. In extensive benchmarking across 54 oncology tasks, including clinical subtyping, grading, mutation prediction, immunohistochemistry status determination, treatment response prediction, and survival prediction, Threads outperformed all baselines while demonstrating remarkable generalizability and label efficiency. It is particularly well suited for predicting rare events, further emphasizing its clinical utility. We intend to make the model publicly available for the broader community.

The field of computational pathology has been transformed with recent advances in foundation models that encode histopathology region-of-interests (ROIs) into versatile and transferable feature representations via self-supervised learning (SSL). However, translating these advancements to address complex clinical challenges at the patient and slide level remains constrained by limited clinical data in disease-specific cohorts, especially for rare clinical conditions. We propose TITAN, a multimodal whole slide foundation model pretrained using 335,645 WSIs via visual self-supervised learning and vision-language alignment with corresponding pathology reports and 423,122 synthetic captions generated from a multimodal generative AI copilot for pathology. Without any finetuning or requiring clinical labels, TITAN can extract general-purpose slide representations and generate pathology reports that generalize to resource-limited clinical scenarios such as rare disease retrieval and cancer prognosis. We evaluate TITAN on diverse clinical tasks and find that TITAN outperforms both ROI and slide foundation models across machine learning settings such as linear probing, few-shot and zero-shot classification, rare cancer retrieval and cross-modal retrieval, and pathology report generation.

Remarkable strides in computational pathology have been made in the task-agnostic foundation model that advances the performance of a wide array of downstream clinical tasks. Despite the promising performance, there are still several challenges. First, prior works have resorted to either vision-only or image-caption data, disregarding pathology reports with more clinically authentic information from pathologists and gene expression profiles which respectively offer distinct knowledge for versatile clinical applications. Second, the current progress in pathology FMs predominantly concentrates on the patch level, where the restricted context of patch-level pretraining fails to capture whole-slide patterns. Even recent slide-level FMs still struggle to provide whole-slide context for patch representation. In this study, for the first time, we develop a pathology foundation model incorporating three levels of modalities: pathology slides, pathology reports, and gene expression data, which resulted in 26,169 slide-level modality pairs from 10,275 patients across 32 cancer types, amounting to over 116 million pathological patch images. To leverage these data for CPath, we propose a novel whole-slide pretraining paradigm that injects the multimodal whole-slide context into the patch representation, called Multimodal Self-TAught PRetraining (mSTAR). The proposed paradigm revolutionizes the pretraining workflow for CPath, enabling the pathology FM to acquire the whole-slide context. To the best of our knowledge, this is the first attempt to incorporate three modalities at the whole-slide context for enhancing pathology FMs. To systematically evaluate the capabilities of mSTAR, we built the largest spectrum of oncological benchmark, spanning 7 categories of oncological applications in 15 types of 97 practical oncological tasks.

With the rapid development of computational pathology, many AI-assisted diagnostic tasks have emerged. Cellular nuclei segmentation can segment various types of cells for downstream analysis, but it relies on predefined categories and lacks flexibility. Moreover, pathology visual question answering can perform image-level understanding but lacks region-level detection capability. To address this, we propose a new benchmark called Pathology Visual Grounding (PathVG), which aims to detect regions based on expressions with different attributes. To evaluate PathVG, we create a new dataset named RefPath which contains 27,610 images with 33,500 language-grounded boxes. Compared to visual grounding in other domains, PathVG presents pathological images at multi-scale and contains expressions with pathological knowledge. In the experimental study, we found that the biggest challenge was the implicit information underlying the pathological expressions. Based on this, we proposed Pathology Knowledge-enhanced Network (PKNet) as the baseline model for PathVG. PKNet leverages the knowledge-enhancement capabilities of Large Language Models (LLMs) to convert pathological terms with implicit information into explicit visual features, and fuses knowledge features with expression features through the designed Knowledge Fusion Module (KFM). The proposed method achieves state-of-the-art performance on the PathVG benchmark.

Advances in foundation modeling have reshaped computational pathology. However, the increasing number of available models and lack of standardized benchmarks make it increasingly complex to assess their strengths, limitations, and potential for further development. To address these challenges, we introduce a new suite of software tools for whole-slide image processing, foundation model benchmarking, and curated publicly available tasks. We anticipate that these resources will promote transparency, reproducibility, and continued progress in the field.

Foundation models are rapidly being developed for computational pathology applications. However, it remains an open question which factors are most important for downstream performance with data scale and diversity, model size, and training algorithm all playing a role. In this work, we present the result of scaling both data and model size, surpassing previous studies in both dimensions, and introduce two new models: Virchow 2, a 632M parameter vision transformer, and Virchow 2G, a 1.85B parameter vision transformer, each trained with 3.1M histopathology whole slide images. To support this scale, we propose domain-inspired adaptations to the DINOv2 training algorithm, which is quickly becoming the default method in self-supervised learning for computational pathology. We achieve state of the art performance on twelve tile-level tasks, as compared to the top performing competing models. Our results suggest that data diversity and domain-specific training can outperform models that only scale in the number of parameters, but, on average, performance benefits from domain-tailoring, data scale, and model scale.

Foundation models pretrained on large-scale datasets are revolutionizing the field of computational pathology (CPath). The generalization ability of foundation models is crucial for the success in various downstream clinical tasks. However, current foundation models have only been evaluated on a limited type and number of tasks, leaving their generalization ability and overall performance unclear. To address this gap, we established a most comprehensive benchmark to evaluate the performance of off-the-shelf foundation models across six distinct clinical task types, encompassing a total of 39 specific tasks. Our findings reveal that existing foundation models excel at certain task types but struggle to effectively handle the full breadth of clinical tasks. To improve the generalization of pathology foundation models, we propose a unified knowledge distillation framework consisting of both expert and self knowledge distillation, where the former allows the model to learn from the knowledge of multiple expert models, while the latter leverages self-distillation to enable image representation learning via local-global alignment. Based on this framework, a Generalizable Pathology Foundation Model (GPFM) is pretrained on a large-scale dataset consisting of 190 million images from around 86,000 public H&E whole slides across 34 major tissue types. Evaluated on the established benchmark, GPFM achieves an impressive average rank of 1.36, with 29 tasks ranked 1st, while the the second-best model, UNI, attains an average rank of 2.96, with only 4 tasks ranked 1st. The superior generalization of GPFM demonstrates its exceptional modeling capabilities across a wide range of clinical tasks, positioning it as a new cornerstone for feature representation in CPath.

Despite the progress made by multimodal large language models (MLLMs) in computational pathology, they remain limited by a predominant focus on patch-level analysis, missing essential contextual information at the whole-slide level. The lack of large-scale instruction datasets and the gigapixel scale of whole slide images (WSIs) pose significant developmental challenges. In this paper, we present SlideChat, the first vision-language assistant capable of understanding gigapixel whole-slide images, exhibiting excellent multimodal conversational capability and response complex instruction across diverse pathology scenarios. To support its development, we created SlideInstruction, the largest instruction-following dataset for WSIs consisting of 4.2K WSI captions and 176K VQA pairs with multiple categories. Furthermore, we propose SlideBench, a multimodal benchmark that incorporates captioning and VQA tasks to assess SlideChat's capabilities in varied clinical settings such as microscopy, diagnosis. Compared to both general and specialized MLLMs, SlideChat exhibits exceptional capabilities achieving state-of-the-art performance on 18 of 22 tasks. For example, it achieved an overall accuracy of 81.17% on SlideBench-VQA (TCGA), and 54.15% on SlideBench-VQA (BCNB). We will fully release SlideChat, SlideInstruction and SlideBench as open-source resources to facilitate research and development in computational pathology.

The use of artificial intelligence to enable precision medicine and decision support systems through the analysis of pathology images has the potential to revolutionize the diagnosis and treatment of cancer. Such applications will depend on models' abilities to capture the diverse patterns observed in pathology images. To address this challenge, we present Virchow, a foundation model for computational pathology. Using self-supervised learning empowered by the DINOv2 algorithm, Virchow is a vision transformer model with 632 million parameters trained on 1.5 million hematoxylin and eosin stained whole slide images from diverse tissue and specimen types, which is orders of magnitude more data than previous works. The Virchow model enables the development of a pan-cancer detection system with 0.949 overall specimen-level AUC across 17 different cancer types, while also achieving 0.937 AUC on 7 rare cancer types. The Virchow model sets the state-of-the-art on the internal and external image tile level benchmarks and slide level biomarker prediction tasks. The gains in performance highlight the importance of training on massive pathology image datasets, suggesting scaling up the data and network architecture can improve the accuracy for many high-impact computational pathology applications where limited amounts of training data are available.

The previous advancements in pathology image understanding primarily involved developing models tailored to specific tasks. Recent studies has demonstrated that the large vision-language model can enhance the performance of various downstream tasks in medical image understanding. In this study, we developed a domain-specific large language-vision assistant (PA-LLaVA) for pathology image understanding. Specifically, (1) we first construct a human pathology image-text dataset by cleaning the public medical image-text data for domain-specific alignment; (2) Using the proposed image-text data, we first train a pathology language-image pretraining (PLIP) model as the specialized visual encoder for pathology image, and then we developed scale-invariant connector to avoid the information loss caused by image scaling; (3) We adopt two-stage learning to train PA-LLaVA, first stage for domain alignment, and second stage for end to end visual question \& answering (VQA) task. In experiments, we evaluate our PA-LLaVA on both supervised and zero-shot VQA datasets, our model achieved the best overall performance among multimodal models of similar scale. The ablation experiments also confirmed the effectiveness of our design. We posit that our PA-LLaVA model and the datasets presented in this work can promote research in field of computational pathology. All codes are available at: https://github.com/ddw2AIGROUP2CQUPT/PA-LLaVA}{https://github.com/ddw2AIGROUP2CQUPT/PA-LLaVA

Developing self-supervised learning (SSL) models that can learn universal and transferable representations of H&E gigapixel whole-slide images (WSIs) is becoming increasingly valuable in computational pathology. These models hold the potential to advance critical tasks such as few-shot classification, slide retrieval, and patient stratification. Existing approaches for slide representation learning extend the principles of SSL from small images (e.g., 224 x 224 patches) to entire slides, usually by aligning two different augmentations (or views) of the slide. Yet the resulting representation remains constrained by the limited clinical and biological diversity of the views. Instead, we postulate that slides stained with multiple markers, such as immunohistochemistry, can be used as different views to form a rich task-agnostic training signal. To this end, we introduce Madeleine, a multimodal pretraining strategy for slide representation learning. Madeleine is trained with a dual global-local cross-stain alignment objective on large cohorts of breast cancer samples (N=4,211 WSIs across five stains) and kidney transplant samples (N=12,070 WSIs across four stains). We demonstrate the quality of slide representations learned by Madeleine on various downstream evaluations, ranging from morphological and molecular classification to prognostic prediction, comprising 21 tasks using 7,299 WSIs from multiple medical centers. Code is available at https://github.com/mahmoodlab/MADELEINE.

Application of deep learning on histopathological whole slide images (WSIs) holds promise of improving diagnostic efficiency and reproducibility but is largely dependent on the ability to write computer code or purchase commercial solutions. We present a code-free pipeline utilizing free-to-use, open-source software (QuPath, DeepMIB, and FastPathology) for creating and deploying deep learning-based segmentation models for computational pathology. We demonstrate the pipeline on a use case of separating epithelium from stroma in colonic mucosa. A dataset of 251 annotated WSIs, comprising 140 hematoxylin-eosin (HE)-stained and 111 CD3 immunostained colon biopsy WSIs, were developed through active learning using the pipeline. On a hold-out test set of 36 HE and 21 CD3-stained WSIs a mean intersection over union score of 96.6% and 95.3% was achieved on epithelium segmentation. We demonstrate pathologist-level segmentation accuracy and clinical acceptable runtime performance and show that pathologists without programming experience can create near state-of-the-art segmentation solutions for histopathological WSIs using only free-to-use software. The study further demonstrates the strength of open-source solutions in its ability to create generalizable, open pipelines, of which trained models and predictions can seamlessly be exported in open formats and thereby used in external solutions. All scripts, trained models, a video tutorial, and the full dataset of 251 WSIs with ~31k epithelium annotations are made openly available at https://github.com/andreped/NoCodeSeg to accelerate research in the field.

Foundation models in computational pathology promise to unlock the development of new clinical decision support systems and models for precision medicine. However, there is a mismatch between most clinical analysis, which is defined at the level of one or more whole slide images, and foundation models to date, which process the thousands of image tiles contained in a whole slide image separately. The requirement to train a network to aggregate information across a large number of tiles in multiple whole slide images limits these models' impact. In this work, we present a slide-level foundation model for H&E-stained histopathology, PRISM, that builds on Virchow tile embeddings and leverages clinical report text for pre-training. Using the tile embeddings, PRISM produces slide-level embeddings with the ability to generate clinical reports, resulting in several modes of use. Using text prompts, PRISM achieves zero-shot cancer detection and sub-typing performance approaching and surpassing that of a supervised aggregator model. Using the slide embeddings with linear classifiers, PRISM surpasses supervised aggregator models. Furthermore, we demonstrate that fine-tuning of the PRISM slide encoder yields label-efficient training for biomarker prediction, a task that typically suffers from low availability of training data; an aggregator initialized with PRISM and trained on as little as 10% of the training data can outperform a supervised baseline that uses all of the data.

The emerging area of computational pathology (CPath) is ripe ground for the application of deep learning (DL) methods to healthcare due to the sheer volume of raw pixel data in whole-slide images (WSIs) of cancerous tissue slides. However, it is imperative for the DL algorithms relying on nuclei-level details to be able to cope with data from `the clinical wild', which tends to be quite challenging. We study, and extend recently released PanNuke dataset consisting of ~200,000 nuclei categorized into 5 clinically important classes for the challenging tasks of segmenting and classifying nuclei in WSIs. Previous pan-cancer datasets consisted of only up to 9 different tissues and up to 21,000 unlabeled nuclei and just over 24,000 labeled nuclei with segmentation masks. PanNuke consists of 19 different tissue types that have been semi-automatically annotated and quality controlled by clinical pathologists, leading to a dataset with statistics similar to the clinical wild and with minimal selection bias. We study the performance of segmentation and classification models when applied to the proposed dataset and demonstrate the application of models trained on PanNuke to whole-slide images. We provide comprehensive statistics about the dataset and outline recommendations and research directions to address the limitations of existing DL tools when applied to real-world CPath applications.

Breast cancer survival prediction in computational pathology presents a remarkable challenge due to tumor heterogeneity. For instance, different regions of the same tumor in the pathology image can show distinct morphological and molecular characteristics. This makes it difficult to extract representative features from whole slide images (WSIs) that truly reflect the tumor's aggressive potential and likely survival outcomes. In this paper, we present PathoHR, a novel pipeline for accurate breast cancer survival prediction that enhances any size of pathological images to enable more effective feature learning. Our approach entails (1) the incorporation of a plug-and-play high-resolution Vision Transformer (ViT) to enhance patch-wise WSI representation, enabling more detailed and comprehensive feature extraction, (2) the systematic evaluation of multiple advanced similarity metrics for comparing WSI-extracted features, optimizing the representation learning process to better capture tumor characteristics, (3) the demonstration that smaller image patches enhanced follow the proposed pipeline can achieve equivalent or superior prediction accuracy compared to raw larger patches, while significantly reducing computational overhead. Experimental findings valid that PathoHR provides the potential way of integrating enhanced image resolution with optimized feature learning to advance computational pathology, offering a promising direction for more accurate and efficient breast cancer survival prediction. Code will be available at https://github.com/AIGeeksGroup/PathoHR.

Object segmentation is an important step in the workflow of computational pathology. Deep learning based models generally require large amount of labeled data for precise and reliable prediction. However, collecting labeled data is expensive because it often requires expert knowledge, particularly in medical imaging domain where labels are the result of a time-consuming analysis made by one or more human experts. As nuclei, cells and glands are fundamental objects for downstream analysis in computational pathology/cytology, in this paper we propose a simple CNN-based approach to speed up collecting annotations for these objects which requires minimum interaction from the annotator. We show that for nuclei and cells in histology and cytology images, one click inside each object is enough for NuClick to yield a precise annotation. For multicellular structures such as glands, we propose a novel approach to provide the NuClick with a squiggle as a guiding signal, enabling it to segment the glandular boundaries. These supervisory signals are fed to the network as auxiliary inputs along with RGB channels. With detailed experiments, we show that NuClick is adaptable to the object scale, robust against variations in the user input, adaptable to new domains, and delivers reliable annotations. An instance segmentation model trained on masks generated by NuClick achieved the first rank in LYON19 challenge. As exemplar outputs of our framework, we are releasing two datasets: 1) a dataset of lymphocyte annotations within IHC images, and 2) a dataset of segmented WBCs in blood smear images.

Instance segmentation and classification of nuclei is an important task in computational pathology. We show that StarDist, a deep learning nuclei segmentation method originally developed for fluorescence microscopy, can be extended and successfully applied to histopathology images. This is substantiated by conducting experiments on the Lizard dataset, and through entering the Colon Nuclei Identification and Counting (CoNIC) challenge 2022, where our approach achieved the first spot on the leaderboard for the segmentation and classification task for both the preliminary and final test phase.

Background: Cancer remains one of the leading causes of morbidity and mortality worldwide. Comprehensive datasets that combine histopathological images with genetic and survival data across various tumour sites are essential for advancing computational pathology and personalised medicine. Results: We present SurGen, a dataset comprising 1,020 H&E-stained whole slide images (WSIs) from 843 colorectal cancer cases. The dataset includes detailed annotations for key genetic mutations (KRAS, NRAS, BRAF) and mismatch repair status, as well as survival data for 426 cases. To demonstrate SurGen's practical utility, we conducted a proof-of-concept machine learning experiment predicting mismatch repair status from the WSIs, achieving a test AUROC of 0.8316. These preliminary results underscore the dataset's potential to facilitate research in biomarker discovery, prognostic modelling, and advanced machine learning applications in colorectal cancer. Conclusions: SurGen offers a valuable resource for the scientific community, enabling studies that require high-quality WSIs linked with comprehensive clinical and genetic information on colorectal cancer. Our initial findings affirm the dataset's capacity to advance diagnostic precision and foster the development of personalised treatment strategies in colorectal oncology. Data available online at https://doi.org/10.6019/S-BIAD1285.

Forensic pathology is critical in determining the cause and manner of death through post-mortem examinations, both macroscopic and microscopic. The field, however, grapples with issues such as outcome variability, laborious processes, and a scarcity of trained professionals. This paper presents SongCi, an innovative visual-language model (VLM) designed specifically for forensic pathology. SongCi utilizes advanced prototypical cross-modal self-supervised contrastive learning to enhance the accuracy, efficiency, and generalizability of forensic analyses. It was pre-trained and evaluated on a comprehensive multi-center dataset, which includes over 16 million high-resolution image patches, 2,228 vision-language pairs of post-mortem whole slide images (WSIs), and corresponding gross key findings, along with 471 distinct diagnostic outcomes. Our findings indicate that SongCi surpasses existing multi-modal AI models in many forensic pathology tasks, performs comparably to experienced forensic pathologists and significantly better than less experienced ones, and provides detailed multi-modal explainability, offering critical assistance in forensic investigations. To the best of our knowledge, SongCi is the first VLM specifically developed for forensic pathological analysis and the first large-vocabulary computational pathology (CPath) model that directly processes gigapixel WSIs in forensic science.

Recent advances in multi-modal algorithms have driven and been driven by the increasing availability of large image-text datasets, leading to significant strides in various fields, including computational pathology. However, in most existing medical image-text datasets, the text typically provides high-level summaries that may not sufficiently describe sub-tile regions within a large pathology image. For example, an image might cover an extensive tissue area containing cancerous and healthy regions, but the accompanying text might only specify that this image is a cancer slide, lacking the nuanced details needed for in-depth analysis. In this study, we introduce STimage-1K4M, a novel dataset designed to bridge this gap by providing genomic features for sub-tile images. STimage-1K4M contains 1,149 images derived from spatial transcriptomics data, which captures gene expression information at the level of individual spatial spots within a pathology image. Specifically, each image in the dataset is broken down into smaller sub-image tiles, with each tile paired with 15,000-30,000 dimensional gene expressions. With 4,293,195 pairs of sub-tile images and gene expressions, STimage-1K4M offers unprecedented granularity, paving the way for a wide range of advanced research in multi-modal data analysis an innovative applications in computational pathology, and beyond.

Nuclear segmentation, classification and quantification within Haematoxylin & Eosin stained histology images enables the extraction of interpretable cell-based features that can be used in downstream explainable models in computational pathology (CPath). However, automatic recognition of different nuclei is faced with a major challenge in that there are several different types of nuclei, some of them exhibiting large intraclass variability. In this work, we propose an approach that combine Separable-HoverNet and Instance-YOLOv5 to indentify colon nuclei small and unbalanced. Our approach can achieve mPQ+ 0.389 on the Segmentation and Classification-Preliminary Test Dataset and r2 0.599 on the Cellular Composition-Preliminary Test Dataset on ISBI 2022 CoNIC Challenge.

The growing volume of high-resolution Whole Slide Images in digital histopathology poses significant storage, transmission, and computational efficiency challenges. Standard compression methods, such as JPEG, reduce file sizes but often fail to preserve fine-grained phenotypic details critical for downstream tasks. In this work, we repurpose autoencoders (AEs) designed for Latent Diffusion Models as an efficient learned compression framework for pathology images. We systematically benchmark three AE models with varying compression levels and evaluate their reconstruction ability using pathology foundation models. We introduce a fine-tuning strategy to further enhance reconstruction fidelity that optimizes a pathology-specific learned perceptual metric. We validate our approach on downstream tasks, including segmentation, patch classification, and multiple instance learning, showing that replacing images with AE-compressed reconstructions leads to minimal performance degradation. Additionally, we propose a K-means clustering-based quantization method for AE latents, improving storage efficiency while maintaining reconstruction quality. We provide the weights of the fine-tuned autoencoders at https://huggingface.co/collections/StonyBrook-CVLab/pathology-fine-tuned-aes-67d45f223a659ff2e3402dd0.

This paper addresses complex challenges in histopathological image analysis through three key contributions. Firstly, it introduces a fast patch selection method, FPS, for whole-slide image (WSI) analysis, significantly reducing computational cost while maintaining accuracy. Secondly, it presents PathDino, a lightweight histopathology feature extractor with a minimal configuration of five Transformer blocks and only 9 million parameters, markedly fewer than alternatives. Thirdly, it introduces a rotation-agnostic representation learning paradigm using self-supervised learning, effectively mitigating overfitting. We also show that our compact model outperforms existing state-of-the-art histopathology-specific vision transformers on 12 diverse datasets, including both internal datasets spanning four sites (breast, liver, skin, and colorectal) and seven public datasets (PANDA, CAMELYON16, BRACS, DigestPath, Kather, PanNuke, and WSSS4LUAD). Notably, even with a training dataset of 6 million histopathology patches from The Cancer Genome Atlas (TCGA), our approach demonstrates an average 8.5% improvement in patch-level majority vote performance. These contributions provide a robust framework for enhancing image analysis in digital pathology, rigorously validated through extensive evaluation. Project Page: https://rhazeslab.github.io/PathDino-Page/

In recent years, the advent of foundation models (FM) for digital pathology has relied heavily on scaling the pre-training datasets and the model size, yielding large and powerful models. While it resulted in improving the performance on diverse downstream tasks, it also introduced increased computational cost and inference time. In this work, we explore the distillation of a large foundation model into a smaller one, reducing the number of parameters by several orders of magnitude. Leveraging distillation techniques, our distilled model, H0-mini, achieves nearly comparable performance to large FMs at a significantly reduced inference cost. It is evaluated on several public benchmarks, achieving 3rd place on the HEST benchmark and 5th place on the EVA benchmark. Additionally, a robustness analysis conducted on the PLISM dataset demonstrates that our distilled model reaches excellent robustness to variations in staining and scanning conditions, significantly outperforming other state-of-the art models. This opens new perspectives to design lightweight and robust models for digital pathology, without compromising on performance.

Transformers exhibit impressive capabilities but are often regarded as black boxes due to challenges in understanding the complex nonlinear relationships between features. Interpreting machine learning models is of paramount importance to mitigate risks, and mechanistic interpretability is in particular of current interest as it opens up a window for guiding manual modifications and reverse-engineering solutions. In this work, we introduce contextual decomposition for transformers (CD-T), extending a prior work on CD for RNNs and CNNs, to address mechanistic interpretation computationally efficiently. CD-T is a flexible interpretation method for transformers. It can capture contributions of combinations of input features or source internal components (e.g. attention heads, feed-forward networks) to (1) final predictions or (2) the output of any target internal component. Using CD-T, we propose a novel algorithm for circuit discovery. On a real-world pathology report classification task: we show CD-T distills a more faithful circuit of attention heads with improved computational efficiency (speed up 2x) than a prior benchmark, path patching. As a versatile interpretation method, CD-T also exhibits exceptional capabilities for local interpretations. CD-T is shown to reliably find words and phrases of contrasting sentiment/topic on SST-2 and AGNews datasets. Through human experiments, we demonstrate CD-T enables users to identify the more accurate of two models and to better trust a model's outputs compared to alternative interpretation methods such as SHAP and LIME.

Whole Slide Image (WSI) classification with multiple instance learning (MIL) in digital pathology faces significant computational challenges. Current methods mostly rely on extensive self-supervised learning (SSL) for satisfactory performance, requiring long training periods and considerable computational resources. At the same time, no pre-training affects performance due to domain shifts from natural images to WSIs. We introduce Snuffy architecture, a novel MIL-pooling method based on sparse transformers that mitigates performance loss with limited pre-training and enables continual few-shot pre-training as a competitive option. Our sparsity pattern is tailored for pathology and is theoretically proven to be a universal approximator with the tightest probabilistic sharp bound on the number of layers for sparse transformers, to date. We demonstrate Snuffy's effectiveness on CAMELYON16 and TCGA Lung cancer datasets, achieving superior WSI and patch-level accuracies. The code is available on https://github.com/jafarinia/snuffy.

Feature vectors provided by pre-trained deep artificial neural networks have become a dominant source for image representation in recent literature. Their contribution to the performance of image analysis can be improved through finetuning. As an ultimate solution, one might even train a deep network from scratch with the domain-relevant images, a highly desirable option which is generally impeded in pathology by lack of labeled images and the computational expense. In this study, we propose a new network, namely KimiaNet, that employs the topology of the DenseNet with four dense blocks, fine-tuned and trained with histopathology images in different configurations. We used more than 240,000 image patches with 1000x1000 pixels acquired at 20x magnification through our proposed "highcellularity mosaic" approach to enable the usage of weak labels of 7,126 whole slide images of formalin-fixed paraffin-embedded human pathology samples publicly available through the The Cancer Genome Atlas (TCGA) repository. We tested KimiaNet using three public datasets, namely TCGA, endometrial cancer images, and colorectal cancer images by evaluating the performance of search and classification when corresponding features of different networks are used for image representation. As well, we designed and trained multiple convolutional batch-normalized ReLU (CBR) networks. The results show that KimiaNet provides superior results compared to the original DenseNet and smaller CBR networks when used as feature extractor to represent histopathology images.

Histopathology plays a central role in clinical medicine and biomedical research. While artificial intelligence shows promising results on many pathological tasks, generalization and dealing with rare diseases, where training data is scarce, remains a challenge. Distilling knowledge from unlabeled data into a foundation model before learning from, potentially limited, labeled data provides a viable path to address these challenges. In this work, we extend the state of the art of foundation models for digital pathology whole slide images by semi-automated data curation and incorporating pathologist domain knowledge. Specifically, we combine computational and pathologist domain knowledge (1) to curate a diverse dataset of 103k slides corresponding to 750 million image patches covering data from different fixation, staining, and scanning protocols as well as data from different indications and labs across the EU and US, (2) for grouping semantically similar slides and tissue patches, and (3) to augment the input images during training. We evaluate the resulting model on a set of public and internal benchmarks and show that although our foundation model is trained with an order of magnitude less slides, it performs on par or better than competing models. We expect that scaling our approach to more data and larger models will further increase its performance and capacity to deal with increasingly complex real world tasks in diagnostics and biomedical research.

Recent advances in vision language models (VLMs) have enabled broad progress in the general medical field. However, pathology still remains a more challenging subdomain, with current pathology specific VLMs exhibiting limitations in both diagnostic accuracy and reasoning plausibility. Such shortcomings are largely attributable to the nature of current pathology datasets, which are primarily composed of image description pairs that lack the depth and structured diagnostic paradigms employed by real world pathologists. In this study, we leverage pathology textbooks and real world pathology experts to construct high-quality, reasoning-oriented datasets. Building on this, we introduce Patho-R1, a multimodal RL-based pathology Reasoner, trained through a three-stage pipeline: (1) continued pretraining on 3.5 million image-text pairs for knowledge infusion; (2) supervised fine-tuning on 500k high-quality Chain-of-Thought samples for reasoning incentivizing; (3) reinforcement learning using Group Relative Policy Optimization and Decoupled Clip and Dynamic sAmpling Policy Optimization strategies for multimodal reasoning quality refinement. To further assess the alignment quality of our dataset, we propose PathoCLIP, trained on the same figure-caption corpus used for continued pretraining. Comprehensive experimental results demonstrate that both PathoCLIP and Patho-R1 achieve robust performance across a wide range of pathology-related tasks, including zero-shot classification, cross-modal retrieval, Visual Question Answering, and Multiple Choice Question. Our project is available at the Patho-R1 repository: https://github.com/Wenchuan-Zhang/Patho-R1.

Pathology text mining is a challenging task given the reporting variability and constant new findings in cancer sub-type definitions. However, successful text mining of a large pathology database can play a critical role to advance 'big data' cancer research like similarity-based treatment selection, case identification, prognostication, surveillance, clinical trial screening, risk stratification, and many others. While there is a growing interest in developing language models for more specific clinical domains, no pathology-specific language space exist to support the rapid data-mining development in pathology space. In literature, a few approaches fine-tuned general transformer models on specialized corpora while maintaining the original tokenizer, but in fields requiring specialized terminology, these models often fail to perform adequately. We propose PathologyBERT - a pre-trained masked language model which was trained on 347,173 histopathology specimen reports and publicly released in the Huggingface repository. Our comprehensive experiments demonstrate that pre-training of transformer model on pathology corpora yields performance improvements on Natural Language Understanding (NLU) and Breast Cancer Diagnose Classification when compared to nonspecific language models.

Pathology is the study of microscopic inspection of tissue, and a pathology diagnosis is often the medical gold standard to diagnose disease. Pathology images provide a unique challenge for computer-vision-based analysis: a single pathology Whole Slide Image (WSI) is gigapixel-sized and often contains hundreds of thousands to millions of objects of interest across multiple resolutions. In this work, we propose PathoLogy Universal TransfOrmer (PLUTO): a light-weight pathology FM that is pre-trained on a diverse dataset of 195 million image tiles collected from multiple sites and extracts meaningful representations across multiple WSI scales that enable a large variety of downstream pathology tasks. In particular, we design task-specific adaptation heads that utilize PLUTO's output embeddings for tasks which span pathology scales ranging from subcellular to slide-scale, including instance segmentation, tile classification, and slide-level prediction. We compare PLUTO's performance to other state-of-the-art methods on a diverse set of external and internal benchmarks covering multiple biologically relevant tasks, tissue types, resolutions, stains, and scanners. We find that PLUTO matches or outperforms existing task-specific baselines and pathology-specific foundation models, some of which use orders-of-magnitude larger datasets and model sizes when compared to PLUTO. Our findings present a path towards a universal embedding to power pathology image analysis, and motivate further exploration around pathology foundation models in terms of data diversity, architectural improvements, sample efficiency, and practical deployability in real-world applications.

Digital pathology enables automatic analysis of histopathological sections using artificial intelligence (AI). Automatic evaluation could improve diagnostic efficiency and help find associations between morphological features and clinical outcome. For development of such prediction models, identifying invasive epithelial cells, and separating these from benign epithelial cells and in situ lesions would be the first step. In this study, we aimed to develop an AI model for segmentation of epithelial cells in sections from breast cancer. We generated epithelial ground truth masks by restaining hematoxylin and eosin (HE) sections with cytokeratin (CK) AE1/AE3, and by pathologists' annotations. HE/CK image pairs were used to train a convolutional neural network, and data augmentation was used to make the model more robust. Tissue microarrays (TMAs) from 839 patients, and whole slide images from two patients were used for training and evaluation of the models. The sections were derived from four cohorts of breast cancer patients. TMAs from 21 patients from a fifth cohort was used as a second test set. In quantitative evaluation, a mean Dice score of 0.70, 0.79, and 0.75 for invasive epithelial cells, benign epithelial cells, and in situ lesions, respectively, were achieved. In qualitative scoring (0-5) by pathologists, results were best for all epithelium and invasive epithelium, with scores of 4.7 and 4.4. Scores for benign epithelium and in situ lesions were 3.7 and 2.0. The proposed model segmented epithelial cells in HE stained breast cancer slides well, but further work is needed for accurate division between the classes. Immunohistochemistry, together with pathologists' annotations, enabled the creation of accurate ground truths. The model is made freely available in FastPathology and the code is available at https://github.com/AICAN-Research/breast-epithelium-segmentation

Pathological diagnosis remains the definitive standard for identifying tumors. The rise of multimodal large models has simplified the process of integrating image analysis with textual descriptions. Despite this advancement, the substantial costs associated with training and deploying these complex multimodal models, together with a scarcity of high-quality training datasets, create a significant divide between cutting-edge technology and its application in the clinical setting. We had meticulously compiled a dataset of approximately 45,000 cases, covering over 6 different tasks, including the classification of organ tissues, generating pathology report descriptions, and addressing pathology-related questions and answers. We have fine-tuned multimodal large models, specifically LLaVA, Qwen-VL, InternLM, with this dataset to enhance instruction-based performance. We conducted a qualitative assessment of the capabilities of the base model and the fine-tuned model in performing image captioning and classification tasks on the specific dataset. The evaluation results demonstrate that the fine-tuned model exhibits proficiency in addressing typical pathological questions. We hope that by making both our models and datasets publicly available, they can be valuable to the medical and research communities.

Pathology, the microscopic examination of diseased tissue, is critical for diagnosing various medical conditions, particularly cancers. Traditional methods are labor-intensive and prone to human error. Digital pathology, which converts glass slides into high-resolution digital images for analysis by computer algorithms, revolutionizes the field by enhancing diagnostic accuracy, consistency, and efficiency through automated image analysis and large-scale data processing. Foundational transformer pretraining is crucial for developing robust, generalizable models as it enables learning from vast amounts of unannotated data. This paper introduces the Hibou family of foundational vision transformers for pathology, leveraging the DINOv2 framework to pretrain two model variants, Hibou-B and Hibou-L, on a proprietary dataset of over 1 million whole slide images (WSIs) representing diverse tissue types and staining techniques. Our pretrained models demonstrate superior performance on both patch-level and slide-level benchmarks, surpassing existing state-of-the-art methods. Notably, Hibou-L achieves the highest average accuracy across multiple benchmark datasets. To support further research and application in the field, we have open-sourced the Hibou-B model, which can be accessed at https://github.com/HistAI/hibou

As advances in large language models (LLMs) and multimodal techniques continue to mature, the development of general-purpose multimodal large language models (MLLMs) has surged, offering significant applications in interpreting natural images. However, the field of pathology has largely remained untapped, particularly in gathering high-quality data and designing comprehensive model frameworks. To bridge the gap in pathology MLLMs, we present PathAsst, a multimodal generative foundation AI assistant to revolutionize diagnostic and predictive analytics in pathology. The development of PathAsst involves three pivotal steps: data acquisition, CLIP model adaptation, and the training of PathAsst's multimodal generative capabilities. Firstly, we collect over 207K high-quality pathology image-text pairs from authoritative sources. Leveraging the advanced power of ChatGPT, we generate over 180K instruction-following samples. Furthermore, we devise additional instruction-following data specifically tailored for invoking eight pathology-specific sub-models we prepared, allowing the PathAsst to effectively collaborate with these models, enhancing its diagnostic ability. Secondly, by leveraging the collected data, we construct PathCLIP, a pathology-dedicated CLIP, to enhance PathAsst's capabilities in interpreting pathology images. Finally, we integrate PathCLIP with the Vicuna-13b and utilize pathology-specific instruction-tuning data to enhance the multimodal generation capacity of PathAsst and bolster its synergistic interactions with sub-models. The experimental results of PathAsst show the potential of harnessing AI-powered generative foundation model to improve pathology diagnosis and treatment processes.

Recent advancements in digital pathology have led to the development of numerous foundational models that utilize self-supervised learning on patches extracted from gigapixel whole slide images (WSIs). While this approach leverages vast amounts of unlabeled data, we have discovered a significant issue: features extracted from these self-supervised models tend to cluster by individual WSIs, a phenomenon we term WSI-specific feature collapse. This problem can potentially limit the model's generalization ability and performance on various downstream tasks. To address this issue, we introduce Stain Normalized Pathology Foundational Model, a novel foundational model trained on patches that have undergone stain normalization. Stain normalization helps reduce color variability arising from different laboratories and scanners, enabling the model to learn more consistent features. Stain Normalized Pathology Foundational Model is trained using 285,153,903 patches extracted from a total of 34,795 WSIs, combining data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project. Our experiments demonstrate that Stain Normalized Pathology Foundational Model significantly mitigates the feature collapse problem, indicating that the model has learned more generalized features rather than overfitting to individual WSI characteristics. We compared Stain Normalized Pathology Foundational Model with state-of-the-art models across six downstream task datasets, and our results show that Stain Normalized Pathology Foundational Model achieves excellent performance relative to the number of WSIs used and the model's parameter count. This suggests that the application of stain normalization has substantially improved the model's efficiency and generalization capabilities.

Vision Language Models (VLMs) like CLIP have attracted substantial attention in pathology, serving as backbones for applications such as zero-shot image classification and Whole Slide Image (WSI) analysis. Additionally, they can function as vision encoders when combined with large language models (LLMs) to support broader capabilities. Current efforts to train pathology VLMs rely on pathology image-text pairs from platforms like PubMed, YouTube, and Twitter, which provide limited, unscalable data with generally suboptimal image quality. In this work, we leverage large-scale WSI datasets like TCGA to extract numerous high-quality image patches. We then train a large multimodal model to generate captions for these images, creating PathGen-1.6M, a dataset containing 1.6 million high-quality image-caption pairs. Our approach involves multiple agent models collaborating to extract representative WSI patches, generating and refining captions to obtain high-quality image-text pairs. Extensive experiments show that integrating these generated pairs with existing datasets to train a pathology-specific CLIP model, PathGen-CLIP, significantly enhances its ability to analyze pathological images, with substantial improvements across nine pathology-related zero-shot image classification tasks and three whole-slide image tasks. Furthermore, we construct 200K instruction-tuning data based on PathGen-1.6M and integrate PathGen-CLIP with the Vicuna LLM to create more powerful multimodal models through instruction tuning. Overall, we provide a scalable pathway for high-quality data generation in pathology, paving the way for next-generation general pathology models.

Radiology reporting generative AI holds significant potential to alleviate clinical workloads and streamline medical care. However, achieving high clinical accuracy is challenging, as radiological images often feature subtle lesions and intricate structures. Existing systems often fall short, largely due to their reliance on fixed size, patch-level image features and insufficient incorporation of pathological information. This can result in the neglect of such subtle patterns and inconsistent descriptions of crucial pathologies. To address these challenges, we propose an innovative approach that leverages pathology-aware regional prompts to explicitly integrate anatomical and pathological information of various scales, significantly enhancing the precision and clinical relevance of generated reports. We develop an anatomical region detector that extracts features from distinct anatomical areas, coupled with a novel multi-label lesion detector that identifies global pathologies. Our approach emulates the diagnostic process of radiologists, producing clinically accurate reports with comprehensive diagnostic capabilities. Experimental results show that our model outperforms previous state-of-the-art methods on most natural language generation and clinical efficacy metrics, with formal expert evaluations affirming its potential to enhance radiology practice.

Recent accelerations in multi-modal applications have been made possible with the plethora of image and text data available online. However, the scarcity of analogous data in the medical field, specifically in histopathology, has halted comparable progress. To enable similar representation learning for histopathology, we turn to YouTube, an untapped resource of videos, offering 1,087 hours of valuable educational histopathology videos from expert clinicians. From YouTube, we curate Quilt: a large-scale vision-language dataset consisting of 768,826 image and text pairs. Quilt was automatically curated using a mixture of models, including large language models, handcrafted algorithms, human knowledge databases, and automatic speech recognition. In comparison, the most comprehensive datasets curated for histopathology amass only around 200K samples. We combine Quilt with datasets from other sources, including Twitter, research papers, and the internet in general, to create an even larger dataset: Quilt-1M, with 1M paired image-text samples, marking it as the largest vision-language histopathology dataset to date. We demonstrate the value of Quilt-1M by fine-tuning a pre-trained CLIP model. Our model outperforms state-of-the-art models on both zero-shot and linear probing tasks for classifying new histopathology images across 13 diverse patch-level datasets of 8 different sub-pathologies and cross-modal retrieval tasks.

Tissue phenotyping is a fundamental task in learning objective characterizations of histopathologic biomarkers within the tumor-immune microenvironment in cancer pathology. However, whole-slide imaging (WSI) is a complex computer vision in which: 1) WSIs have enormous image resolutions with precludes large-scale pixel-level efforts in data curation, and 2) diversity of morphological phenotypes results in inter- and intra-observer variability in tissue labeling. To address these limitations, current efforts have proposed using pretrained image encoders (transfer learning from ImageNet, self-supervised pretraining) in extracting morphological features from pathology, but have not been extensively validated. In this work, we conduct a search for good representations in pathology by training a variety of self-supervised models with validation on a variety of weakly-supervised and patch-level tasks. Our key finding is in discovering that Vision Transformers using DINO-based knowledge distillation are able to learn data-efficient and interpretable features in histology images wherein the different attention heads learn distinct morphological phenotypes. We make evaluation code and pretrained weights publicly-available at: https://github.com/Richarizardd/Self-Supervised-ViT-Path.

Driven by the recent advances in deep learning methods and, in particular, by the development of modern self-supervised learning algorithms, increased interest and efforts have been devoted to build foundation models (FMs) for medical images. In this work, we present our scalable training pipeline for large pathology imaging data, and a comprehensive analysis of various hyperparameter choices and training techniques for building pathology FMs. We release and make publicly available the first batch of our pathology FMs (https://github.com/kaiko-ai/towards_large_pathology_fms) trained on open-access TCGA whole slide images, a commonly used collection of pathology images. The experimental evaluation shows that our models reach state-of-the-art performance on various patch-level downstream tasks, ranging from breast cancer subtyping to colorectal nuclear segmentation. Finally, to unify the evaluation approaches used in the field and to simplify future comparisons of different FMs, we present an open-source framework (https://github.com/kaiko-ai/eva) designed for the consistent evaluation of pathology FMs across various downstream tasks.

The emergence of large multimodal models has unlocked remarkable potential in AI, particularly in pathology. However, the lack of specialized, high-quality benchmark impeded their development and precise evaluation. To address this, we introduce PathMMU, the largest and highest-quality expert-validated pathology benchmark for LMMs. It comprises 33,573 multimodal multi-choice questions and 21,599 images from various sources, and an explanation for the correct answer accompanies each question. The construction of PathMMU capitalizes on the robust capabilities of GPT-4V, utilizing approximately 30,000 gathered image-caption pairs to generate Q\&As. Significantly, to maximize PathMMU's authority, we invite six pathologists to scrutinize each question under strict standards in PathMMU's validation and test sets, while simultaneously setting an expert-level performance benchmark for PathMMU. We conduct extensive evaluations, including zero-shot assessments of 14 open-sourced and three closed-sourced LMMs and their robustness to image corruption. We also fine-tune representative LMMs to assess their adaptability to PathMMU. The empirical findings indicate that advanced LMMs struggle with the challenging PathMMU benchmark, with the top-performing LMM, GPT-4V, achieving only a 51.7\% zero-shot performance, significantly lower than the 71.4\% demonstrated by human pathologists. After fine-tuning, even open-sourced LMMs can surpass GPT-4V with a performance of over 60\%, but still fall short of the expertise shown by pathologists. We hope that the PathMMU will offer valuable insights and foster the development of more specialized, next-generation LLMs for pathology.

While machine learning is currently transforming the field of histopathology, the domain lacks a comprehensive evaluation of state-of-the-art models based on essential but complementary quality requirements beyond a mere classification accuracy. In order to fill this gap, we developed a new methodology to extensively evaluate a wide range of classification models, including recent vision transformers, and convolutional neural networks such as: ConvNeXt, ResNet (BiT), Inception, ViT and Swin transformer, with and without supervised or self-supervised pretraining. We thoroughly tested the models on five widely used histopathology datasets containing whole slide images of breast, gastric, and colorectal cancer and developed a novel approach using an image-to-image translation model to assess the robustness of a cancer classification model against stain variations. Further, we extended existing interpretability methods to previously unstudied models and systematically reveal insights of the models' classifications strategies that can be transferred to future model architectures.

Tumor synthesis can generate examples that AI often misses or over-detects, improving AI performance by training on these challenging cases. However, existing synthesis methods, which are typically unconditional -- generating images from random variables -- or conditioned only by tumor shapes, lack controllability over specific tumor characteristics such as texture, heterogeneity, boundaries, and pathology type. As a result, the generated tumors may be overly similar or duplicates of existing training data, failing to effectively address AI's weaknesses. We propose a new text-driven tumor synthesis approach, termed TextoMorph, that provides textual control over tumor characteristics. This is particularly beneficial for examples that confuse the AI the most, such as early tumor detection (increasing Sensitivity by +8.5%), tumor segmentation for precise radiotherapy (increasing DSC by +6.3%), and classification between benign and malignant tumors (improving Sensitivity by +8.2%). By incorporating text mined from radiology reports into the synthesis process, we increase the variability and controllability of the synthetic tumors to target AI's failure cases more precisely. Moreover, TextoMorph uses contrastive learning across different texts and CT scans, significantly reducing dependence on scarce image-report pairs (only 141 pairs used in this study) by leveraging a large corpus of 34,035 radiology reports. Finally, we have developed rigorous tests to evaluate synthetic tumors, including Text-Driven Visual Turing Test and Radiomics Pattern Analysis, showing that our synthetic tumors is realistic and diverse in texture, heterogeneity, boundaries, and pathology.

Deep convolutional neural networks (CNNs) are the current state-of-the-art for digital analysis of histopathological images. The large size of whole-slide microscopy images (WSIs) requires advanced memory handling to read, display and process these images. There are several open-source platforms for working with WSIs, but few support deployment of CNN models. These applications use third-party solutions for inference, making them less user-friendly and unsuitable for high-performance image analysis. To make deployment of CNNs user-friendly and feasible on low-end machines, we have developed a new platform, FastPathology, using the FAST framework and C++. It minimizes memory usage for reading and processing WSIs, deployment of CNN models, and real-time interactive visualization of results. Runtime experiments were conducted on four different use cases, using different architectures, inference engines, hardware configurations and operating systems. Memory usage for reading, visualizing, zooming and panning a WSI were measured, using FastPathology and three existing platforms. FastPathology performed similarly in terms of memory to the other C++ based application, while using considerably less than the two Java-based platforms. The choice of neural network model, inference engine, hardware and processors influenced runtime considerably. Thus, FastPathology includes all steps needed for efficient visualization and processing of WSIs in a single application, including inference of CNNs with real-time display of the results. Source code, binary releases and test data can be found online on GitHub at https://github.com/SINTEFMedtek/FAST-Pathology/.

Considering the increased workload in pathology laboratories today, automated tools such as artificial intelligence models can help pathologists with their tasks and ease the workload. In this paper, we are proposing a segmentation model (DRU-Net) that can provide a delineation of human non-small cell lung carcinomas and an augmentation method that can improve classification results. The proposed model is a fused combination of truncated pre-trained DenseNet201 and ResNet101V2 as a patch-wise classifier followed by a lightweight U-Net as a refinement model. We have used two datasets (Norwegian Lung Cancer Biobank and Haukeland University Hospital lung cancer cohort) to create our proposed model. The DRU-Net model achieves an average of 0.91 Dice similarity coefficient. The proposed spatial augmentation method (multi-lens distortion) improved the network performance by 3%. Our findings show that choosing image patches that specifically include regions of interest leads to better results for the patch-wise classifier compared to other sampling methods. The qualitative analysis showed that the DRU-Net model is generally successful in detecting the tumor. On the test set, some of the cases showed areas of false positive and false negative segmentation in the periphery, particularly in tumors with inflammatory and reactive changes.

Metadata are general characteristics of the data in a well-curated and condensed format, and have been proven to be useful for decision making, knowledge discovery, and also heterogeneous data organization of biobank. Among all data types in the biobank, pathology is the key component of the biobank and also serves as the gold standard of diagnosis. To maximize the utility of biobank and allow the rapid progress of biomedical science, it is essential to organize the data with well-populated pathology metadata. However, manual annotation of such information is tedious and time-consuming. In the study, we develop a multimodal multitask learning framework to predict four major slide-level metadata of pathology images. The framework learns generalizable representations across tissue slides, pathology reports, and case-level structured data. We demonstrate improved performance across all four tasks with the proposed method compared to a single modal single task baseline on two test sets, one external test set from a distinct data source (TCGA) and one internal held-out test set (TTH). In the test sets, the performance improvements on the averaged area under receiver operating characteristic curve across the four tasks are 16.48% and 9.05% on TCGA and TTH, respectively. Such pathology metadata prediction system may be adopted to mitigate the effort of expert annotation and ultimately accelerate the data-driven research by better utilization of the pathology biobank.

Deep learning has enabled the development of highly robust foundation models for various pathological tasks across diverse diseases and patient cohorts. Among these models, vision-language pre-training, which leverages large-scale paired data to align pathology image and text embedding spaces, and provides a novel zero-shot paradigm for downstream tasks. However, existing models have been primarily data-driven and lack the incorporation of domain-specific knowledge, which limits their performance in cancer diagnosis, especially for rare tumor subtypes. To address this limitation, we establish a Knowledge-enhanced Pathology (KEEP) foundation model that harnesses disease knowledge to facilitate vision-language pre-training. Specifically, we first construct a disease knowledge graph (KG) that covers 11,454 human diseases with 139,143 disease attributes, including synonyms, definitions, and hypernym relations. We then systematically reorganize the millions of publicly available noisy pathology image-text pairs, into 143K well-structured semantic groups linked through the hierarchical relations of the disease KG. To derive more nuanced image and text representations, we propose a novel knowledge-enhanced vision-language pre-training approach that integrates disease knowledge into the alignment within hierarchical semantic groups instead of unstructured image-text pairs. Validated on 18 diverse benchmarks with more than 14,000 whole slide images (WSIs), KEEP achieves state-of-the-art performance in zero-shot cancer diagnostic tasks. Notably, for cancer detection, KEEP demonstrates an average sensitivity of 89.8% at a specificity of 95.0% across 7 cancer types. For cancer subtyping, KEEP achieves a median balanced accuracy of 0.456 in subtyping 30 rare brain cancers, indicating strong generalizability for diagnosing rare tumors.

Histopathology has played an essential role in cancer diagnosis. With the rapid advances in convolutional neural networks (CNN). Various CNN-based automated pathological image segmentation approaches have been developed in computer-assisted pathological image analysis. In the past few years, Transformer neural networks (Transformer) have shown the unique merit of capturing the global long-distance dependencies across the entire image as a new deep learning paradigm. Such merit is appealing for exploring spatially heterogeneous pathological images. However, there have been very few, if any, studies that have systematically evaluated the current Transformer-based approaches in pathological image segmentation. To assess the performance of Transformer segmentation models on whole slide images (WSI), we quantitatively evaluated six prevalent transformer-based models on tumor segmentation, using the widely used PAIP liver histopathological dataset. For a more comprehensive analysis, we also compare the transformer-based models with six major traditional CNN-based models. The results show that the Transformer-based models exhibit a general superior performance over the CNN-based models. In particular, Segmenter, Swin-Transformer and TransUNet-all transformer-based-came out as the best performers among the twelve evaluated models.

In this paper we present a hybrid method for the automatic detection of dermatological pathologies in medical reports. We use a large language model combined with medical ontologies to predict, given a first appointment or follow-up medical report, the pathology a person may suffer from. The results show that teaching the model to learn the type, severity and location on the body of a dermatological pathology, as well as in which order it has to learn these three features, significantly increases its accuracy. The article presents the demonstration of state-of-the-art results for classification of medical texts with a precision of 0.84, micro and macro F1-score of 0.82 and 0.75, and makes both the method and the data set used available to the community.

Pathology Foundation Models (FMs) hold great promise for healthcare. Before they can be used in clinical practice, it is essential to ensure they are robust to variations between medical centers. We measure whether pathology FMs focus on biological features like tissue and cancer type, or on the well known confounding medical center signatures introduced by staining procedure and other differences. We introduce the Robustness Index. This novel robustness metric reflects to what degree biological features dominate confounding features. Ten current publicly available pathology FMs are evaluated. We find that all current pathology foundation models evaluated represent the medical center to a strong degree. Significant differences in the robustness index are observed. Only one model so far has a robustness index greater than one, meaning biological features dominate confounding features, but only slightly. A quantitative approach to measure the influence of medical center differences on FM-based prediction performance is described. We analyze the impact of unrobustness on classification performance of downstream models, and find that cancer-type classification errors are not random, but specifically attributable to same-center confounders: images of other classes from the same medical center. We visualize FM embedding spaces, and find these are more strongly organized by medical centers than by biological factors. As a consequence, the medical center of origin is predicted more accurately than the tissue source and cancer type. The robustness index introduced here is provided with the aim of advancing progress towards clinical adoption of robust and reliable pathology FMs.

Vision foundation models (FMs) are accelerating the development of digital pathology algorithms and transforming biomedical research. These models learn, in a self-supervised manner, to represent histological features in highly heterogeneous tiles extracted from whole-slide images (WSIs) of real-world patient samples. The performance of these FMs is significantly influenced by the size, diversity, and balance of the pre-training data. However, data selection has been primarily guided by expert knowledge at the WSI level, focusing on factors such as disease classification and tissue types, while largely overlooking the granular details available at the tile level. In this paper, we investigate the potential of unsupervised automatic data curation at the tile-level, taking into account 350 million tiles. Specifically, we apply hierarchical clustering trees to pre-extracted tile embeddings, allowing us to sample balanced datasets uniformly across the embedding space of the pretrained FM. We further identify these datasets are subject to a trade-off between size and balance, potentially compromising the quality of representations learned by FMs, and propose tailored batch sampling strategies to mitigate this effect. We demonstrate the effectiveness of our method through improved performance on a diverse range of clinically relevant downstream tasks.

Computational microscopy, in which hardware and algorithms of an imaging system are jointly designed, shows promise for making imaging systems that cost less, perform more robustly, and collect new types of information. Often, the performance of computational imaging systems, especially those that incorporate machine learning, is sample-dependent. Thus, standardized datasets are an essential tool for comparing the performance of different approaches. Here, we introduce the Berkeley Single Cell Computational Microscopy (BSCCM) dataset, which contains over ~12,000,000 images of 400,000 of individual white blood cells. The dataset contains images captured with multiple illumination patterns on an LED array microscope and fluorescent measurements of the abundance of surface proteins that mark different cell types. We hope this dataset will provide a valuable resource for the development and testing of new algorithms in computational microscopy and computer vision with practical biomedical applications.

Is it possible to develop an "AI Pathologist" to pass the board-certified examination of the American Board of Pathology? To achieve this goal, the first step is to create a visual question answering (VQA) dataset where the AI agent is presented with a pathology image together with a question and is asked to give the correct answer. Our work makes the first attempt to build such a dataset. Different from creating general-domain VQA datasets where the images are widely accessible and there are many crowdsourcing workers available and capable of generating question-answer pairs, developing a medical VQA dataset is much more challenging. First, due to privacy concerns, pathology images are usually not publicly available. Second, only well-trained pathologists can understand pathology images, but they barely have time to help create datasets for AI research. To address these challenges, we resort to pathology textbooks and online digital libraries. We develop a semi-automated pipeline to extract pathology images and captions from textbooks and generate question-answer pairs from captions using natural language processing. We collect 32,799 open-ended questions from 4,998 pathology images where each question is manually checked to ensure correctness. To our best knowledge, this is the first dataset for pathology VQA. Our dataset will be released publicly to promote research in medical VQA.

The recent surge in performance for image analysis of digitised pathology slides can largely be attributed to the advances in deep learning. Deep models can be used to initially localise various structures in the tissue and hence facilitate the extraction of interpretable features for biomarker discovery. However, these models are typically trained for a single task and therefore scale poorly as we wish to adapt the model for an increasing number of different tasks. Also, supervised deep learning models are very data hungry and therefore rely on large amounts of training data to perform well. In this paper, we present a multi-task learning approach for segmentation and classification of nuclei, glands, lumina and different tissue regions that leverages data from multiple independent data sources. While ensuring that our tasks are aligned by the same tissue type and resolution, we enable meaningful simultaneous prediction with a single network. As a result of feature sharing, we also show that the learned representation can be used to improve the performance of additional tasks via transfer learning, including nuclear classification and signet ring cell detection. As part of this work, we train our developed Cerberus model on a huge amount of data, consisting of over 600K objects for segmentation and 440K patches for classification. We use our approach to process 599 colorectal whole-slide images from TCGA, where we localise 377 million, 900K and 2.1 million nuclei, glands and lumina, respectively and make the results available to the community for downstream analysis.

Task-specific deep learning models in histopathology offer promising opportunities for improving diagnosis, clinical research, and precision medicine. However, development of such models is often limited by availability of high-quality data. Foundation models in histopathology that learn general representations across a wide range of tissue types, diagnoses, and magnifications offer the potential to reduce the data, compute, and technical expertise necessary to develop task-specific deep learning models with the required level of model performance. In this work, we describe the development and evaluation of foundation models for histopathology via self-supervised learning (SSL). We first establish a diverse set of benchmark tasks involving 17 unique tissue types and 12 unique cancer types and spanning different optimal magnifications and task types. Next, we use this benchmark to explore and evaluate histopathology-specific SSL methods followed by further evaluation on held out patch-level and weakly supervised tasks. We found that standard SSL methods thoughtfully applied to histopathology images are performant across our benchmark tasks and that domain-specific methodological improvements can further increase performance. Our findings reinforce the value of using domain-specific SSL methods in pathology, and establish a set of high quality foundation models to enable further research across diverse applications.

Survival prediction is a complicated ordinal regression task that aims to predict the ranking risk of death, which generally benefits from the integration of histology and genomic data. Despite the progress in joint learning from pathology and genomics, existing methods still suffer from challenging issues: 1) Due to the large size of pathological images, it is difficult to effectively represent the gigapixel whole slide images (WSIs). 2) Interactions within tumor microenvironment (TME) in histology are essential for survival analysis. Although current approaches attempt to model these interactions via co-attention between histology and genomic data, they focus on only dense local similarity across modalities, which fails to capture global consistency between potential structures, i.e. TME-related interactions of histology and co-expression of genomic data. To address these challenges, we propose a Multimodal Optimal Transport-based Co-Attention Transformer framework with global structure consistency, in which optimal transport (OT) is applied to match patches of a WSI and genes embeddings for selecting informative patches to represent the gigapixel WSI. More importantly, OT-based co-attention provides a global awareness to effectively capture structural interactions within TME for survival prediction. To overcome high computational complexity of OT, we propose a robust and efficient implementation over micro-batch of WSI patches by approximating the original OT with unbalanced mini-batch OT. Extensive experiments show the superiority of our method on five benchmark datasets compared to the state-of-the-art methods. The code is released.

Pathogen identification is pivotal in diagnosing, treating, and preventing diseases, crucial for controlling infections and safeguarding public health. Traditional alignment-based methods, though widely used, are computationally intense and reliant on extensive reference databases, often failing to detect novel pathogens due to their low sensitivity and specificity. Similarly, conventional machine learning techniques, while promising, require large annotated datasets and extensive feature engineering and are prone to overfitting. Addressing these challenges, we introduce PathoLM, a cutting-edge pathogen language model optimized for the identification of pathogenicity in bacterial and viral sequences. Leveraging the strengths of pre-trained DNA models such as the Nucleotide Transformer, PathoLM requires minimal data for fine-tuning, thereby enhancing pathogen detection capabilities. It effectively captures a broader genomic context, significantly improving the identification of novel and divergent pathogens. We developed a comprehensive data set comprising approximately 30 species of viruses and bacteria, including ESKAPEE pathogens, seven notably virulent bacterial strains resistant to antibiotics. Additionally, we curated a species classification dataset centered specifically on the ESKAPEE group. In comparative assessments, PathoLM dramatically outperforms existing models like DciPatho, demonstrating robust zero-shot and few-shot capabilities. Furthermore, we expanded PathoLM-Sp for ESKAPEE species classification, where it showed superior performance compared to other advanced deep learning methods, despite the complexities of the task.

Histopathological cancer diagnostics has become more complex, and the increasing number of biopsies is a challenge for most pathology laboratories. Thus, development of automatic methods for evaluation of histopathological cancer sections would be of value. In this study, we used 624 whole slide images (WSIs) of breast cancer from a Norwegian cohort. We propose a cascaded convolutional neural network design, called H2G-Net, for semantic segmentation of gigapixel histopathological images. The design involves a detection stage using a patch-wise method, and a refinement stage using a convolutional autoencoder. To validate the design, we conducted an ablation study to assess the impact of selected components in the pipeline on tumour segmentation. Guiding segmentation, using hierarchical sampling and deep heatmap refinement, proved to be beneficial when segmenting the histopathological images. We found a significant improvement when using a refinement network for postprocessing the generated tumour segmentation heatmaps. The overall best design achieved a Dice score of 0.933 on an independent test set of 90 WSIs. The design outperformed single-resolution approaches, such as cluster-guided, patch-wise high-resolution classification using MobileNetV2 (0.872) and a low-resolution U-Net (0.874). In addition, segmentation on a representative x400 WSI took ~58 seconds, using only the CPU. The findings demonstrate the potential of utilizing a refinement network to improve patch-wise predictions. The solution is efficient and does not require overlapping patch inference or ensembling. Furthermore, we showed that deep neural networks can be trained using a random sampling scheme that balances on multiple different labels simultaneously, without the need of storing patches on disk. Future work should involve more efficient patch generation and sampling, as well as improved clustering.

In hematology, computational models offer significant potential to improve diagnostic accuracy, streamline workflows, and reduce the tedious work of analyzing single cells in peripheral blood or bone marrow smears. However, clinical adoption of computational models has been hampered by the lack of generalization due to large batch effects, small dataset sizes, and poor performance in transfer learning from natural images. To address these challenges, we introduce DinoBloom, the first foundation model for single cell images in hematology, utilizing a tailored DINOv2 pipeline. Our model is built upon an extensive collection of 13 diverse, publicly available datasets of peripheral blood and bone marrow smears, the most substantial open-source cohort in hematology so far, comprising over 380,000 white blood cell images. To assess its generalization capability, we evaluate it on an external dataset with a challenging domain shift. We show that our model outperforms existing medical and non-medical vision models in (i) linear probing and k-nearest neighbor evaluations for cell-type classification on blood and bone marrow smears and (ii) weakly supervised multiple instance learning for acute myeloid leukemia subtyping by a large margin. A family of four DinoBloom models (small, base, large, and giant) can be adapted for a wide range of downstream applications, be a strong baseline for classification problems, and facilitate the assessment of batch effects in new datasets. All models are available at github.com/marrlab/DinoBloom.

Multiple Instance learning (MIL) models have been extensively used in pathology to predict biomarkers and risk-stratify patients from gigapixel-sized images. Machine learning problems in medical imaging often deal with rare diseases, making it important for these models to work in a label-imbalanced setting. In pathology images, there is another level of imbalance, where given a positively labeled Whole Slide Image (WSI), only a fraction of pixels within it contribute to the positive label. This compounds the severity of imbalance and makes imbalanced classification in pathology challenging. Furthermore, these imbalances can occur in out-of-distribution (OOD) datasets when the models are deployed in the real-world. We leverage the idea that decoupling feature and classifier learning can lead to improved decision boundaries for label imbalanced datasets. To this end, we investigate the integration of supervised contrastive learning with multiple instance learning (SC-MIL). Specifically, we propose a joint-training MIL framework in the presence of label imbalance that progressively transitions from learning bag-level representations to optimal classifier learning. We perform experiments with different imbalance settings for two well-studied problems in cancer pathology: subtyping of non-small cell lung cancer and subtyping of renal cell carcinoma. SC-MIL provides large and consistent improvements over other techniques on both in-distribution (ID) and OOD held-out sets across multiple imbalanced settings.

Cancer is a complex disease, the understanding and treatment of which are being aided through increases in the volume of collected data and in the scale of deployed computing power. Consequently, there is a growing need for the development of data-driven and, in particular, deep learning methods for various tasks such as cancer diagnosis, detection, prognosis, and prediction. Despite recent successes, however, designing high-performing deep learning models for nonimage and nontext cancer data is a time-consuming, trial-and-error, manual task that requires both cancer domain and deep learning expertise. To that end, we develop a reinforcement-learning-based neural architecture search to automate deep-learning-based predictive model development for a class of representative cancer data. We develop custom building blocks that allow domain experts to incorporate the cancer-data-specific characteristics. We show that our approach discovers deep neural network architectures that have significantly fewer trainable parameters, shorter training time, and accuracy similar to or higher than those of manually designed architectures. We study and demonstrate the scalability of our approach on up to 1,024 Intel Knights Landing nodes of the Theta supercomputer at the Argonne Leadership Computing Facility.

Understanding how deep learning models predict oncology patient risk can provide critical insights into disease progression, support clinical decision-making, and pave the way for trustworthy and data-driven precision medicine. Building on recent advances in the spatial modeling of the tumor microenvironment using graph neural networks, we present an explainable cell graph (xCG) approach for survival prediction. We validate our model on a public cohort of imaging mass cytometry (IMC) data for 416 cases of lung adenocarcinoma. We explain survival predictions in terms of known phenotypes on the cell level by computing risk attributions over cell graphs, for which we propose an efficient grid-based layer-wise relevance propagation (LRP) method. Our ablation studies highlight the importance of incorporating the cancer stage and model ensembling to improve the quality of risk estimates. Our xCG method, together with the IMC data, is made publicly available to support further research.

Artificial intelligence-assisted imaging analysis has made substantial strides in tumor diagnosis and management. Here we present PASTA, a pan-tumor CT foundation model that achieves state-of-the-art performance on 45 of 46 representative oncology tasks -- including lesion segmentation, tumor detection in plain CT, tumor staging, survival prediction, structured report generation, and cross-modality transfer learning, significantly outperforming the second-best models on 35 tasks. This remarkable advancement is driven by our development of PASTA-Gen, an innovative synthetic tumor generation framework that produces a comprehensive dataset of 30,000 CT scans with pixel-level annotated lesions and paired structured reports, encompassing malignancies across ten organs and five benign lesion types. By leveraging this rich, high-quality synthetic data, we overcome a longstanding bottleneck in the development of CT foundation models -- specifically, the scarcity of publicly available, high-quality annotated datasets due to privacy constraints and the substantial labor required for scaling precise data annotation. Encouragingly, PASTA demonstrates exceptional data efficiency with promising practical value, markedly improving performance on various tasks with only a small amount of real-world data. The open release of both the synthetic dataset and PASTA foundation model effectively addresses the challenge of data scarcity, thereby advancing oncological research and clinical translation.

We propose a new model for digital pathology segmentation, based on the observation that histopathology images are inherently symmetric under rotation and reflection. Utilizing recent findings on rotation equivariant CNNs, the proposed model leverages these symmetries in a principled manner. We present a visual analysis showing improved stability on predictions, and demonstrate that exploiting rotation equivariance significantly improves tumor detection performance on a challenging lymph node metastases dataset. We further present a novel derived dataset to enable principled comparison of machine learning models, in combination with an initial benchmark. Through this dataset, the task of histopathology diagnosis becomes accessible as a challenging benchmark for fundamental machine learning research.

Pancreatic cancer is one of the leading causes of cancer-related death. Accurate detection, segmentation, and differential diagnosis of the full taxonomy of pancreatic lesions, i.e., normal, seven major types of lesions, and other lesions, is critical to aid the clinical decision-making of patient management and treatment. However, existing works focus on segmentation and classification for very specific lesion types (PDAC) or groups. Moreover, none of the previous work considers using lesion prevalence-related non-imaging patient information to assist the differential diagnosis. To this end, we develop a meta-information-aware dual-path transformer and exploit the feasibility of classification and segmentation of the full taxonomy of pancreatic lesions. Specifically, the proposed method consists of a CNN-based segmentation path (S-path) and a transformer-based classification path (C-path). The S-path focuses on initial feature extraction by semantic segmentation using a UNet-based network. The C-path utilizes both the extracted features and meta-information for patient-level classification based on stacks of dual-path transformer blocks that enhance the modeling of global contextual information. A large-scale multi-phase CT dataset of 3,096 patients with pathology-confirmed pancreatic lesion class labels, voxel-wise manual annotations of lesions from radiologists, and patient meta-information, was collected for training and evaluations. Our results show that our method can enable accurate classification and segmentation of the full taxonomy of pancreatic lesions, approaching the accuracy of the radiologist's report and significantly outperforming previous baselines. Results also show that adding the common meta-information, i.e., gender and age, can boost the model's performance, thus demonstrating the importance of meta-information for aiding pancreatic disease diagnosis.

Gene expression can be used to subtype breast cancer with improved prediction of risk of recurrence and treatment responsiveness over that obtained using routine immunohistochemistry (IHC). However, in the clinic, molecular profiling is primarily used for ER+ breast cancer, which is costly, tissue destructive, requires specialized platforms and takes several weeks to obtain a result. Deep learning algorithms can effectively extract morphological patterns in digital histopathology images to predict molecular phenotypes quickly and cost-effectively. We propose a new, computationally efficient approach called hist2RNA inspired by bulk RNA-sequencing techniques to predict the expression of 138 genes (incorporated from six commercially available molecular profiling tests), including luminal PAM50 subtype, from hematoxylin and eosin (H&E) stained whole slide images (WSIs). The training phase involves the aggregation of extracted features for each patient from a pretrained model to predict gene expression at the patient level using annotated H&E images from The Cancer Genome Atlas (TCGA, n=335). We demonstrate successful gene prediction on a held-out test set (n = 160, corr = 0.82 across patients, corr = 0.29 across genes) and perform exploratory analysis on an external tissue microarray (TMA) dataset (n = 498) with known IHC and survival information. Our model is able to predict gene expression and luminal PAM50 subtype (Luminal A versus Luminal B) on the TMA dataset with prognostic significance for overall survival in univariate analysis (c-index = 0.56, hazard ratio = 2.16 (95% CI 1.12-3.06), p < 5 x 10-3), and independent significance in multivariate analysis incorporating standard clinicopathological variables (c-index = 0.65, hazard ratio = 1.85 (95% CI 1.30-2.68), p < 5 x 10-3).

Disease progression simulation is a crucial area of research that has significant implications for clinical diagnosis, prognosis, and treatment. One major challenge in this field is the lack of continuous medical imaging monitoring of individual patients over time. To address this issue, we develop a novel framework termed Progressive Image Editing (PIE) that enables controlled manipulation of disease-related image features, facilitating precise and realistic disease progression simulation. Specifically, we leverage recent advancements in text-to-image generative models to simulate disease progression accurately and personalize it for each patient. We theoretically analyze the iterative refining process in our framework as a gradient descent with an exponentially decayed learning rate. To validate our framework, we conduct experiments in three medical imaging domains. Our results demonstrate the superiority of PIE over existing methods such as Stable Diffusion Walk and Style-Based Manifold Extrapolation based on CLIP score (Realism) and Disease Classification Confidence (Alignment). Our user study collected feedback from 35 veteran physicians to assess the generated progressions. Remarkably, 76.2% of the feedback agrees with the fidelity of the generated progressions. To our best knowledge, PIE is the first of its kind to generate disease progression images meeting real-world standards. It is a promising tool for medical research and clinical practice, potentially allowing healthcare providers to model disease trajectories over time, predict future treatment responses, and improve patient outcomes.

Cell instance segmentation in cytology images has significant importance for biology analysis and cancer screening, while remains challenging due to 1) the extensive overlapping translucent cell clusters that cause the ambiguous boundaries, and 2) the confusion of mimics and debris as nuclei. In this work, we proposed a De-overlapping Network (DoNet) in a decompose-and-recombined strategy. A Dual-path Region Segmentation Module (DRM) explicitly decomposes the cell clusters into intersection and complement regions, followed by a Semantic Consistency-guided Recombination Module (CRM) for integration. To further introduce the containment relationship of the nucleus in the cytoplasm, we design a Mask-guided Region Proposal Strategy (MRP) that integrates the cell attention maps for inner-cell instance prediction. We validate the proposed approach on ISBI2014 and CPS datasets. Experiments show that our proposed DoNet significantly outperforms other state-of-the-art (SOTA) cell instance segmentation methods. The code is available at https://github.com/DeepDoNet/DoNet.

Human readers or radiologists routinely perform full-body multi-organ multi-disease detection and diagnosis in clinical practice, while most medical AI systems are built to focus on single organs with a narrow list of a few diseases. This might severely limit AI's clinical adoption. A certain number of AI models need to be assembled non-trivially to match the diagnostic process of a human reading a CT scan. In this paper, we construct a Unified Tumor Transformer (UniT) model to detect (tumor existence and location) and diagnose (tumor characteristics) eight major cancer-prevalent organs in CT scans. UniT is a query-based Mask Transformer model with the output of multi-organ and multi-tumor semantic segmentation. We decouple the object queries into organ queries, detection queries and diagnosis queries, and further establish hierarchical relationships among the three groups. This clinically-inspired architecture effectively assists inter- and intra-organ representation learning of tumors and facilitates the resolution of these complex, anatomically related multi-organ cancer image reading tasks. UniT is trained end-to-end using a curated large-scale CT images of 10,042 patients including eight major types of cancers and occurring non-cancer tumors (all are pathology-confirmed with 3D tumor masks annotated by radiologists). On the test set of 631 patients, UniT has demonstrated strong performance under a set of clinically relevant evaluation metrics, substantially outperforming both multi-organ segmentation methods and an assembly of eight single-organ expert models in tumor detection, segmentation, and diagnosis. Such a unified multi-cancer image reading model (UniT) can significantly reduce the number of false positives produced by combined multi-system models. This moves one step closer towards a universal high-performance cancer screening tool.

An increasing number of public datasets have shown a marked impact on automated organ segmentation and tumor detection. However, due to the small size and partially labeled problem of each dataset, as well as a limited investigation of diverse types of tumors, the resulting models are often limited to segmenting specific organs/tumors and ignore the semantics of anatomical structures, nor can they be extended to novel domains. To address these issues, we propose the CLIP-Driven Universal Model, which incorporates text embedding learned from Contrastive Language-Image Pre-training (CLIP) to segmentation models. This CLIP-based label encoding captures anatomical relationships, enabling the model to learn a structured feature embedding and segment 25 organs and 6 types of tumors. The proposed model is developed from an assembly of 14 datasets, using a total of 3,410 CT scans for training and then evaluated on 6,162 external CT scans from 3 additional datasets. We rank first on the Medical Segmentation Decathlon (MSD) public leaderboard and achieve state-of-the-art results on Beyond The Cranial Vault (BTCV). Additionally, the Universal Model is computationally more efficient (6x faster) compared with dataset-specific models, generalized better to CT scans from varying sites, and shows stronger transfer learning performance on novel tasks.

Pathology diagnosis based on EEG signals and decoding brain activity holds immense importance in understanding neurological disorders. With the advancement of artificial intelligence methods and machine learning techniques, the potential for accurate data-driven diagnoses and effective treatments has grown significantly. However, applying machine learning algorithms to real-world datasets presents diverse challenges at multiple levels. The scarcity of labelled data, especially in low regime scenarios with limited availability of real patient cohorts due to high costs of recruitment, underscores the vital deployment of scaling and transfer learning techniques. In this study, we explore a real-world pathology classification task to highlight the effectiveness of data and model scaling and cross-dataset knowledge transfer. As such, we observe varying performance improvements through data scaling, indicating the need for careful evaluation and labelling. Additionally, we identify the challenges of possible negative transfer and emphasize the significance of some key components to overcome distribution shifts and potential spurious correlations and achieve positive transfer. We see improvement in the performance of the target model on the target (NMT) datasets by using the knowledge from the source dataset (TUAB) when a low amount of labelled data was available. Our findings indicate a small and generic model (e.g. ShallowNet) performs well on a single dataset, however, a larger model (e.g. TCN) performs better on transfer and learning from a larger and diverse dataset.

We present a deep learning segmentation model that can automatically and robustly segment all major anatomical structures in body CT images. In this retrospective study, 1204 CT examinations (from the years 2012, 2016, and 2020) were used to segment 104 anatomical structures (27 organs, 59 bones, 10 muscles, 8 vessels) relevant for use cases such as organ volumetry, disease characterization, and surgical or radiotherapy planning. The CT images were randomly sampled from routine clinical studies and thus represent a real-world dataset (different ages, pathologies, scanners, body parts, sequences, and sites). The authors trained an nnU-Net segmentation algorithm on this dataset and calculated Dice similarity coefficients (Dice) to evaluate the model's performance. The trained algorithm was applied to a second dataset of 4004 whole-body CT examinations to investigate age dependent volume and attenuation changes. The proposed model showed a high Dice score (0.943) on the test set, which included a wide range of clinical data with major pathologies. The model significantly outperformed another publicly available segmentation model on a separate dataset (Dice score, 0.932 versus 0.871, respectively). The aging study demonstrated significant correlations between age and volume and mean attenuation for a variety of organ groups (e.g., age and aortic volume; age and mean attenuation of the autochthonous dorsal musculature). The developed model enables robust and accurate segmentation of 104 anatomical structures. The annotated dataset (https://doi.org/10.5281/zenodo.6802613) and toolkit (https://www.github.com/wasserth/TotalSegmentator) are publicly available.

We demonstrate that AI models can accurately segment liver tumors without the need for manual annotation by using synthetic tumors in CT scans. Our synthetic tumors have two intriguing advantages: (I) realistic in shape and texture, which even medical professionals can confuse with real tumors; (II) effective for training AI models, which can perform liver tumor segmentation similarly to the model trained on real tumors -- this result is exciting because no existing work, using synthetic tumors only, has thus far reached a similar or even close performance to real tumors. This result also implies that manual efforts for annotating tumors voxel by voxel (which took years to create) can be significantly reduced in the future. Moreover, our synthetic tumors can automatically generate many examples of small (or even tiny) synthetic tumors and have the potential to improve the success rate of detecting small liver tumors, which is critical for detecting the early stages of cancer. In addition to enriching the training data, our synthesizing strategy also enables us to rigorously assess the AI robustness.

The gigapixel scale of whole slide images (WSIs) poses a challenge for histopathology multi-modal chatbots, requiring a global WSI analysis for diagnosis, compounding evidence from different WSI patches. Current visual instruction datasets, generated through large language models, focus on creating question/answer pairs for individual image patches, which may lack diagnostic capacity on their own in histopathology, further complicated by the absence of spatial grounding in histopathology image captions. To bridge this gap, we introduce Quilt-Instruct, a large-scale dataset of 107,131 histopathology-specific instruction question/answer pairs, that is collected by leveraging educational histopathology videos from YouTube, which provides spatial localization of captions by automatically extracting narrators' cursor movements. In addition, we provide contextual reasoning by extracting diagnosis and supporting facts from the entire video content to guide the extrapolative reasoning of GPT-4. Using Quilt-Instruct, we train Quilt-LLaVA, which can reason beyond the given single image patch, enabling diagnostic reasoning and the capability of spatial awareness. To evaluate Quilt-LLaVA, we propose a comprehensive evaluation dataset created from 985 images and 1283 human-generated question-answers. We also thoroughly evaluate Quilt-LLaVA using public histopathology datasets, where Quilt-LLaVA significantly outperforms SOTA by over 10% on relative GPT-4 score and 4% and 9% on open and closed set VQA. Our code, data, and model are publicly available at quilt-llava.github.io.

Solving the inverse problem is the key step in evaluating the capacity of a physical model to describe real phenomena. In medical image computing, it aligns with the classical theme of image-based model personalization. Traditionally, a solution to the problem is obtained by performing either sampling or variational inference based methods. Both approaches aim to identify a set of free physical model parameters that results in a simulation best matching an empirical observation. When applied to brain tumor modeling, one of the instances of image-based model personalization in medical image computing, the overarching drawback of the methods is the time complexity for finding such a set. In a clinical setting with limited time between imaging and diagnosis or even intervention, this time complexity may prove critical. As the history of quantitative science is the history of compression, we align in this paper with the historical tendency and propose a method compressing complex traditional strategies for solving an inverse problem into a simple database query task. We evaluated different ways of performing the database query task assessing the trade-off between accuracy and execution time. On the exemplary task of brain tumor growth modeling, we prove that the proposed method achieves one order speed-up compared to existing approaches for solving the inverse problem. The resulting compute time offers critical means for relying on more complex and, hence, realistic models, for integrating image preprocessing and inverse modeling even deeper, or for implementing the current model into a clinical workflow.

Representation learning of pathology whole-slide images (WSIs) has primarily relied on weak supervision with Multiple Instance Learning (MIL). This approach leads to slide representations highly tailored to a specific clinical task. Self-supervised learning (SSL) has been successfully applied to train histopathology foundation models (FMs) for patch embedding generation. However, generating patient or slide level embeddings remains challenging. Existing approaches for slide representation learning extend the principles of SSL from patch level learning to entire slides by aligning different augmentations of the slide or by utilizing multimodal data. By integrating tile embeddings from multiple FMs, we propose a new single modality SSL method in feature space that generates useful slide representations. Our contrastive pretraining strategy, called COBRA, employs multiple FMs and an architecture based on Mamba-2. COBRA exceeds performance of state-of-the-art slide encoders on four different public CPTAC cohorts on average by at least +3.8% AUC, despite only being pretrained on 3048 WSIs from TCGA. Additionally, COBRA is readily compatible at inference time with previously unseen feature extractors.

To synthesize high-fidelity samples, diffusion models typically require auxiliary data to guide the generation process. However, it is impractical to procure the painstaking patch-level annotation effort required in specialized domains like histopathology and satellite imagery; it is often performed by domain experts and involves hundreds of millions of patches. Modern-day self-supervised learning (SSL) representations encode rich semantic and visual information. In this paper, we posit that such representations are expressive enough to act as proxies to fine-grained human labels. We introduce a novel approach that trains diffusion models conditioned on embeddings from SSL. Our diffusion models successfully project these features back to high-quality histopathology and remote sensing images. In addition, we construct larger images by assembling spatially consistent patches inferred from SSL embeddings, preserving long-range dependencies. Augmenting real data by generating variations of real images improves downstream classifier accuracy for patch-level and larger, image-scale classification tasks. Our models are effective even on datasets not encountered during training, demonstrating their robustness and generalizability. Generating images from learned embeddings is agnostic to the source of the embeddings. The SSL embeddings used to generate a large image can either be extracted from a reference image, or sampled from an auxiliary model conditioned on any related modality (e.g. class labels, text, genomic data). As proof of concept, we introduce the text-to-large image synthesis paradigm where we successfully synthesize large pathology and satellite images out of text descriptions.

Extraction of relevant pathological terms from radiology reports is important for correct image label generation and disease population studies. In this letter, we compare the performance of some known application program interface (APIs) for the task of thoracic abnormality extraction from radiology reports. We explored several medical domain specific annotation tools like Medical Text Indexer(MTI) with Non-MEDLINE and Mesh On Demand(MOD) options and generic Natural Language Understanding (NLU) API provided by the IBM cloud. Our results show that although MTI and MOD are intended for extracting medical terms, their performance is worst compared to generic extraction API like IBM NLU. Finally, we trained a DNN-based Named Entity Recognition (NER) model to extract the key concept words from radiology reports. Our model outperforms the medical specific and generic API performance by a large margin. Our results demonstrate the inadequacy of generic APIs for pathology extraction task and establish the importance of domain specific model training for improved results. We hope that these results motivate the research community to release larger de-identified radiology reports corpus for building high accuracy machine learning models for the important task of pathology extraction.

To generate evidence regarding the safety and efficacy of artificial intelligence (AI) enabled medical devices, AI models need to be evaluated on a diverse population of patient cases, some of which may not be readily available. We propose an evaluation approach for testing medical imaging AI models that relies on in silico imaging pipelines in which stochastic digital models of human anatomy (in object space) with and without pathology are imaged using a digital replica imaging acquisition system to generate realistic synthetic image datasets. Here, we release M-SYNTH, a dataset of cohorts with four breast fibroglandular density distributions imaged at different exposure levels using Monte Carlo x-ray simulations with the publicly available Virtual Imaging Clinical Trial for Regulatory Evaluation (VICTRE) toolkit. We utilize the synthetic dataset to analyze AI model performance and find that model performance decreases with increasing breast density and increases with higher mass density, as expected. As exposure levels decrease, AI model performance drops with the highest performance achieved at exposure levels lower than the nominal recommended dose for the breast type.

Development of artificial intelligence (AI) techniques in medical imaging requires access to large-scale and diverse datasets for training and evaluation. In dermatology, obtaining such datasets remains challenging due to significant variations in patient populations, illumination conditions, and acquisition system characteristics. In this work, we propose S-SYNTH, the first knowledge-based, adaptable open-source skin simulation framework to rapidly generate synthetic skin, 3D models and digitally rendered images, using an anatomically inspired multi-layer, multi-component skin and growing lesion model. The skin model allows for controlled variation in skin appearance, such as skin color, presence of hair, lesion shape, and blood fraction among other parameters. We use this framework to study the effect of possible variations on the development and evaluation of AI models for skin lesion segmentation, and show that results obtained using synthetic data follow similar comparative trends as real dermatologic images, while mitigating biases and limitations from existing datasets including small dataset size, lack of diversity, and underrepresentation.

Medical images and radiology reports are crucial for diagnosing medical conditions, highlighting the importance of quantitative analysis for clinical decision-making. However, the diversity and cross-source heterogeneity of these data challenge the generalizability of current data-mining methods. Multimodal large language models (MLLMs) have recently transformed many domains, significantly affecting the medical field. Notably, Gemini-Vision-series (Gemini) and GPT-4-series (GPT-4) models have epitomized a paradigm shift in Artificial General Intelligence (AGI) for computer vision, showcasing their potential in the biomedical domain. In this study, we evaluated the performance of the Gemini, GPT-4, and 4 popular large models for an exhaustive evaluation across 14 medical imaging datasets, including 5 medical imaging categories (dermatology, radiology, dentistry, ophthalmology, and endoscopy), and 3 radiology report datasets. The investigated tasks encompass disease classification, lesion segmentation, anatomical localization, disease diagnosis, report generation, and lesion detection. Our experimental results demonstrated that Gemini-series models excelled in report generation and lesion detection but faces challenges in disease classification and anatomical localization. Conversely, GPT-series models exhibited proficiency in lesion segmentation and anatomical localization but encountered difficulties in disease diagnosis and lesion detection. Additionally, both the Gemini series and GPT series contain models that have demonstrated commendable generation efficiency. While both models hold promise in reducing physician workload, alleviating pressure on limited healthcare resources, and fostering collaboration between clinical practitioners and artificial intelligence technologies, substantial enhancements and comprehensive validations remain imperative before clinical deployment.

Histopathology and transcriptomics are fundamental modalities in oncology, encapsulating the morphological and molecular aspects of the disease. Multi-modal self-supervised learning has demonstrated remarkable potential in learning pathological representations by integrating diverse data sources. Conventional multi-modal integration methods primarily emphasize modality alignment, while paying insufficient attention to retaining the modality-specific structures. However, unlike conventional scenarios where multi-modal inputs share highly overlapping features, histopathology and transcriptomics exhibit pronounced heterogeneity, offering orthogonal yet complementary insights. Histopathology provides morphological and spatial context, elucidating tissue architecture and cellular topology, whereas transcriptomics delineates molecular signatures through gene expression patterns. This inherent disparity introduces a major challenge in aligning them while maintaining modality-specific fidelity. To address these challenges, we present MIRROR, a novel multi-modal representation learning method designed to foster both modality alignment and retention. MIRROR employs dedicated encoders to extract comprehensive features for each modality, which is further complemented by a modality alignment module to achieve seamless integration between phenotype patterns and molecular profiles. Furthermore, a modality retention module safeguards unique attributes from each modality, while a style clustering module mitigates redundancy and enhances disease-relevant information by modeling and aligning consistent pathological signatures within a clustering space. Extensive evaluations on TCGA cohorts for cancer subtyping and survival analysis highlight MIRROR's superior performance, demonstrating its effectiveness in constructing comprehensive oncological feature representations and benefiting the cancer diagnosis.

Background: General-purpose large language models that utilize both text and images have not been evaluated on a diverse array of challenging medical cases. Methods: Using 934 cases from the NEJM Image Challenge published between 2005 and 2023, we evaluated the accuracy of the recently released Generative Pre-trained Transformer 4 with Vision model (GPT-4V) compared to human respondents overall and stratified by question difficulty, image type, and skin tone. We further conducted a physician evaluation of GPT-4V on 69 NEJM clinicopathological conferences (CPCs). Analyses were conducted for models utilizing text alone, images alone, and both text and images. Results: GPT-4V achieved an overall accuracy of 61% (95% CI, 58 to 64%) compared to 49% (95% CI, 49 to 50%) for humans. GPT-4V outperformed humans at all levels of difficulty and disagreement, skin tones, and image types; the exception was radiographic images, where performance was equivalent between GPT-4V and human respondents. Longer, more informative captions were associated with improved performance for GPT-4V but similar performance for human respondents. GPT-4V included the correct diagnosis in its differential for 80% (95% CI, 68 to 88%) of CPCs when using text alone, compared to 58% (95% CI, 45 to 70%) of CPCs when using both images and text. Conclusions: GPT-4V outperformed human respondents on challenging medical cases and was able to synthesize information from both images and text, but performance deteriorated when images were added to highly informative text. Overall, our results suggest that multimodal AI models may be useful in medical diagnostic reasoning but that their accuracy may depend heavily on context.

In breast cancer imaging, there has been a trend to directly predict pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) from histological images based on deep learning (DL). However, it has been a commonly known problem that the constructed DL-based models numerically have better performances in internal validation than in external validation. The primary reason for this situation lies in that the distribution of the external data for validation is different from the distribution of the training data for the construction of the predictive model. In this paper, we aim to alleviate this situation with a more intrinsic approach. We propose an experts' cognition-driven ensemble deep learning (ECDEDL) approach for external validation of predicting pCR to NAC from histological images in breast cancer. The proposed ECDEDL, which takes the cognition of both pathology and artificial intelligence experts into consideration to improve the generalization of the predictive model to the external validation, more intrinsically approximates the working paradigm of a human being which will refer to his various working experiences to make decisions. The proposed ECDEDL approach was validated with 695 WSIs collected from the same center as the primary dataset to develop the predictive model and perform the internal validation, and 340 WSIs collected from other three centers as the external dataset to perform the external validation. In external validation, the proposed ECDEDL approach improves the AUCs of pCR prediction from 61.52(59.80-63.26) to 67.75(66.74-68.80) and the Accuracies of pCR prediction from 56.09(49.39-62.79) to 71.01(69.44-72.58). The proposed ECDEDL was quite effective for external validation, numerically more approximating the internal validation.

Quantitative susceptibility maps from magnetic resonance images can provide both prognostic and diagnostic information in multiple sclerosis, a neurodegenerative disease characterized by the formation of lesions in white matter brain tissue. In particular, susceptibility maps provide adequate contrast to distinguish between "rim" lesions, surrounded by deposited paramagnetic iron, and "non-rim" lesion types. These paramagnetic rim lesions (PRLs) are an emerging biomarker in multiple sclerosis. Much effort has been devoted to both detection and segmentation of such lesions to monitor longitudinal change. As paramagnetic rim lesions are rare, addressing this problem requires confronting the class imbalance between rim and non-rim lesions. We produce synthetic quantitative susceptibility maps of paramagnetic rim lesions and show that inclusion of such synthetic data improves classifier performance and provide a multi-channel extension to generate accompanying contrasts and probabilistic segmentation maps. We exploit the projection capability of our trained generative network to demonstrate a novel denoising approach that allows us to train on ambiguous rim cases and substantially increase the minority class. We show that both synthetic lesion synthesis and our proposed rim lesion label denoising method best approximate the unseen rim lesion distribution and improve detection in a clinically interpretable manner. We release our code and generated data at https://github.com/agr78/PRLx-GAN upon publication.

Prostate cancer, a growing global health concern, necessitates precise diagnostic tools, with Magnetic Resonance Imaging (MRI) offering high-resolution soft tissue imaging that significantly enhances diagnostic accuracy. Recent advancements in explainable AI and representation learning have significantly improved prostate cancer diagnosis by enabling automated and precise lesion classification. However, existing explainable AI methods, particularly those based on frameworks like generative adversarial networks (GANs), are predominantly developed for natural image generation, and their application to medical imaging often leads to suboptimal performance due to the unique characteristics and complexity of medical image. To address these challenges, our paper introduces three key contributions. First, we propose ProjectedEx, a generative framework that provides interpretable, multi-attribute explanations, effectively linking medical image features to classifier decisions. Second, we enhance the encoder module by incorporating feature pyramids, which enables multiscale feedback to refine the latent space and improves the quality of generated explanations. Additionally, we conduct comprehensive experiments on both the generator and classifier, demonstrating the clinical relevance and effectiveness of ProjectedEx in enhancing interpretability and supporting the adoption of AI in medical settings. Code will be released at https://github.com/Richardqiyi/ProjectedEx

Deep neural networks have introduced significant advancements in the field of machine learning-based analysis of digital pathology images including prostate tissue images. With the help of transfer learning, classification and segmentation performance of neural network models have been further increased. However, due to the absence of large, extensively annotated, publicly available prostate histopathology datasets, several previous studies employ datasets from well-studied computer vision tasks such as ImageNet dataset. In this work, we propose a transfer learning scheme from breast histopathology images to improve prostate cancer detection performance. We validate our approach on annotated prostate whole slide images by using a publicly available breast histopathology dataset as pre-training. We show that the proposed cross-cancer approach outperforms transfer learning from ImageNet dataset.

With the rapid advances in high-throughput sequencing technologies, the focus of survival analysis has shifted from examining clinical indicators to incorporating genomic profiles with pathological images. However, existing methods either directly adopt a straightforward fusion of pathological features and genomic profiles for survival prediction, or take genomic profiles as guidance to integrate the features of pathological images. The former would overlook intrinsic cross-modal correlations. The latter would discard pathological information irrelevant to gene expression. To address these issues, we present a Cross-Modal Translation and Alignment (CMTA) framework to explore the intrinsic cross-modal correlations and transfer potential complementary information. Specifically, we construct two parallel encoder-decoder structures for multi-modal data to integrate intra-modal information and generate cross-modal representation. Taking the generated cross-modal representation to enhance and recalibrate intra-modal representation can significantly improve its discrimination for comprehensive survival analysis. To explore the intrinsic crossmodal correlations, we further design a cross-modal attention module as the information bridge between different modalities to perform cross-modal interactions and transfer complementary information. Our extensive experiments on five public TCGA datasets demonstrate that our proposed framework outperforms the state-of-the-art methods.

Breast cancer is a significant health concern affecting millions of women worldwide. Accurate survival risk stratification plays a crucial role in guiding personalised treatment decisions and improving patient outcomes. Here we present BioFusionNet, a deep learning framework that fuses image-derived features with genetic and clinical data to achieve a holistic patient profile and perform survival risk stratification of ER+ breast cancer patients. We employ multiple self-supervised feature extractors, namely DINO and MoCoV3, pretrained on histopathology patches to capture detailed histopathological image features. We then utilise a variational autoencoder (VAE) to fuse these features, and harness the latent space of the VAE to feed into a self-attention network, generating patient-level features. Next, we develop a co-dual-cross-attention mechanism to combine the histopathological features with genetic data, enabling the model to capture the interplay between them. Additionally, clinical data is incorporated using a feed-forward network (FFN), further enhancing predictive performance and achieving comprehensive multimodal feature integration. Furthermore, we introduce a weighted Cox loss function, specifically designed to handle imbalanced survival data, which is a common challenge in the field. The proposed model achieves a mean concordance index (C-index) of 0.77 and a time-dependent area under the curve (AUC) of 0.84, outperforming state-of-the-art methods. It predicts risk (high versus low) with prognostic significance for overall survival (OS) in univariate analysis (HR=2.99, 95% CI: 1.88--4.78, p<0.005), and maintains independent significance in multivariate analysis incorporating standard clinicopathological variables (HR=2.91, 95% CI: 1.80--4.68, p<0.005). The proposed method not only improves model performance but also addresses a critical gap in handling imbalanced data.

Breast cancer is a prevalent form of cancer among women, with over 1.5 million women being diagnosed each year. Unfortunately, the survival rates for breast cancer patients in certain third-world countries, like South Africa, are alarmingly low, with only 40% of diagnosed patients surviving beyond five years. The inadequate availability of resources, including qualified pathologists, delayed diagnoses, and ineffective therapy planning, contribute to this low survival rate. To address this pressing issue, medical specialists and researchers have turned to domain-specific AI approaches, specifically deep learning models, to develop end-to-end solutions that can be integrated into computer-aided diagnosis (CAD) systems. By improving the workflow of pathologists, these AI models have the potential to enhance the detection and diagnosis of breast cancer. This research focuses on evaluating the performance of various cutting-edge convolutional neural network (CNN) architectures in comparison to a relatively new model called the Vision Trans-former (ViT). The objective is to determine the superiority of these models in terms of their accuracy and effectiveness. The experimental results reveal that the ViT models outperform the other selected state-of-the-art CNN architectures, achieving an impressive accuracy rate of 95.15%. This study signifies a significant advancement in the field, as it explores the utilization of data augmentation and other relevant preprocessing techniques in conjunction with deep learning models for the detection and diagnosis of breast cancer using datasets of Breast Cancer Histopathological Image Classification.

Masked image modelling (MIM) is a powerful self-supervised representation learning paradigm, whose potential has not been widely demonstrated in medical image analysis. In this work, we show the capacity of MIM to capture rich semantic representations of Haemotoxylin & Eosin (H&E)-stained images at the nuclear level. Inspired by Bidirectional Encoder representation from Image Transformers (BEiT), we split the images into smaller patches and generate corresponding discrete visual tokens. In addition to the regular grid-based patches, typically used in visual Transformers, we introduce patches of individual cell nuclei. We propose positional encoding of the irregular distribution of these structures within an image. We pre-train the model in a self-supervised manner on H&E-stained whole-slide images of diffuse large B-cell lymphoma, where cell nuclei have been segmented. The pre-training objective is to recover the original discrete visual tokens of the masked image on the one hand, and to reconstruct the visual tokens of the masked object instances on the other. Coupling these two pre-training tasks allows us to build powerful, context-aware representations of nuclei. Our model generalizes well and can be fine-tuned on downstream classification tasks, achieving improved cell classification accuracy on PanNuke dataset by more than 5% compared to current instance segmentation methods.

The visual examination of tissue biopsy sections is fundamental for cancer diagnosis, with pathologists analyzing sections at multiple magnifications to discern tumor cells and their subtypes. However, existing attention-based multiple instance learning (MIL) models, used for analyzing Whole Slide Images (WSIs) in cancer diagnostics, often overlook the contextual information of tumor and neighboring tiles, leading to misclassifications. To address this, we propose the Context-Aware Multiple Instance Learning (CAMIL) architecture. CAMIL incorporates neighbor-constrained attention to consider dependencies among tiles within a WSI and integrates contextual constraints as prior knowledge into the MIL model. We evaluated CAMIL on subtyping non-small cell lung cancer (TCGA-NSCLC) and detecting lymph node (CAMELYON16) metastasis, achieving test AUCs of 0.959\% and 0.975\%, respectively, outperforming other state-of-the-art methods. Additionally, CAMIL enhances model interpretability by identifying regions of high diagnostic value.

Recent advances in microscopy have enabled the rapid generation of terabytes of image data in cell biology and biomedical research. Vision-language models (VLMs) offer a promising solution for large-scale biological image analysis, enhancing researchers' efficiency, identifying new image biomarkers, and accelerating hypothesis generation and scientific discovery. However, there is a lack of standardized, diverse, and large-scale vision-language benchmarks to evaluate VLMs' perception and cognition capabilities in biological image understanding. To address this gap, we introduce {\mu}-Bench, an expert-curated benchmark encompassing 22 biomedical tasks across various scientific disciplines (biology, pathology), microscopy modalities (electron, fluorescence, light), scales (subcellular, cellular, tissue), and organisms in both normal and abnormal states. We evaluate state-of-the-art biomedical, pathology, and general VLMs on {\mu}-Bench and find that: i) current models struggle on all categories, even for basic tasks such as distinguishing microscopy modalities; ii) current specialist models fine-tuned on biomedical data often perform worse than generalist models; iii) fine-tuning in specific microscopy domains can cause catastrophic forgetting, eroding prior biomedical knowledge encoded in their base model. iv) weight interpolation between fine-tuned and pre-trained models offers one solution to forgetting and improves general performance across biomedical tasks. We release {\mu}-Bench under a permissive license to accelerate the research and development of microscopy foundation models.

With over 85 million CT scans performed annually in the United States, creating tumor-related reports is a challenging and time-consuming task for radiologists. To address this need, we present RadGPT, an Anatomy-Aware Vision-Language AI Agent for generating detailed reports from CT scans. RadGPT first segments tumors, including benign cysts and malignant tumors, and their surrounding anatomical structures, then transforms this information into both structured reports and narrative reports. These reports provide tumor size, shape, location, attenuation, volume, and interactions with surrounding blood vessels and organs. Extensive evaluation on unseen hospitals shows that RadGPT can produce accurate reports, with high sensitivity/specificity for small tumor (<2 cm) detection: 80/73% for liver tumors, 92/78% for kidney tumors, and 77/77% for pancreatic tumors. For large tumors, sensitivity ranges from 89% to 97%. The results significantly surpass the state-of-the-art in abdominal CT report generation. RadGPT generated reports for 17 public datasets. Through radiologist review and refinement, we have ensured the reports' accuracy, and created the first publicly available image-text 3D medical dataset, comprising over 1.8 million text tokens and 2.7 million images from 9,262 CT scans, including 2,947 tumor scans/reports of 8,562 tumor instances. Our reports can: (1) localize tumors in eight liver sub-segments and three pancreatic sub-segments annotated per-voxel; (2) determine pancreatic tumor stage (T1-T4) in 260 reports; and (3) present individual analyses of multiple tumors--rare in human-made reports. Importantly, 948 of the reports are for early-stage tumors.

The differential diagnosis of neurodegenerative dementias is a challenging clinical task, mainly because of the overlap in symptom presentation and the similarity of patterns observed in structural neuroimaging. To improve diagnostic efficiency and accuracy, deep learning-based methods such as Convolutional Neural Networks and Vision Transformers have been proposed for the automatic classification of brain MRIs. However, despite their strong predictive performance, these models find limited clinical utility due to their opaque decision making. In this work, we propose a framework that integrates two core components to enhance diagnostic transparency. First, we introduce a modular pipeline for converting 3D T1-weighted brain MRIs into textual radiology reports. Second, we explore the potential of modern Large Language Models (LLMs) to assist clinicians in the differential diagnosis between Frontotemporal dementia subtypes, Alzheimer's disease, and normal aging based on the generated reports. To bridge the gap between predictive accuracy and explainability, we employ reinforcement learning to incentivize diagnostic reasoning in LLMs. Without requiring supervised reasoning traces or distillation from larger models, our approach enables the emergence of structured diagnostic rationales grounded in neuroimaging findings. Unlike post-hoc explainability methods that retrospectively justify model decisions, our framework generates diagnostic rationales as part of the inference process-producing causally grounded explanations that inform and guide the model's decision-making process. In doing so, our framework matches the diagnostic performance of existing deep learning methods while offering rationales that support its diagnostic conclusions.

Medical systematic reviews can be very costly and resource intensive. We explore how Large Language Models (LLMs) can support and be trained to perform literature screening when provided with a detailed set of selection criteria. Specifically, we instruction tune LLaMA and Guanaco models to perform abstract screening for medical systematic reviews. Our best model, Bio-SIEVE, outperforms both ChatGPT and trained traditional approaches, and generalises better across medical domains. However, there remains the challenge of adapting the model to safety-first scenarios. We also explore the impact of multi-task training with Bio-SIEVE-Multi, including tasks such as PICO extraction and exclusion reasoning, but find that it is unable to match single-task Bio-SIEVE's performance. We see Bio-SIEVE as an important step towards specialising LLMs for the biomedical systematic review process and explore its future developmental opportunities. We release our models, code and a list of DOIs to reconstruct our dataset for reproducibility.

Colorectal cancer is one of the most common cancers worldwide, so early pathological examination is very important. However, it is time-consuming and labor-intensive to identify the number and type of cells on H&E images in clinical. Therefore, automatic segmentation and classification task and counting the cellular composition of H&E images from pathological sections is proposed by CoNIC Challenge 2022. We proposed a multi-scale Swin transformer with HTC for this challenge, and also applied the known normalization methods to generate more augmentation data. Finally, our strategy showed that the multi-scale played a crucial role to identify different scale features and the augmentation arose the recognition of model.

Despite being self-supervised, protein language models have shown remarkable performance in fundamental biological tasks such as predicting impact of genetic variation on protein structure and function. The effectiveness of these models on diverse set of tasks suggests that they learn meaningful representations of fitness landscape that can be useful for downstream clinical applications. Here, we interrogate the use of these language models in characterizing known pathogenic mutations in curated, medically actionable genes through an exhaustive search of putative compensatory mutations on each variant's genetic background. Systematic analysis of the predicted effects of these compensatory mutations reveal unappreciated structural features of proteins that are missed by other structure predictors like AlphaFold. While deep mutational scan experiments provide an unbiased estimate of the mutational landscape, we encourage the community to generate and curate rescue mutation experiments to inform the design of more sophisticated co-masking strategies and leverage large language models more effectively for downstream clinical prediction tasks.

Robust and accurate detection and segmentation of heterogenous tumors appearing in different anatomical organs with supervised methods require large-scale labeled datasets covering all possible types of diseases. Due to the unavailability of such rich datasets and the high cost of annotations, unsupervised anomaly detection (UAD) methods have been developed aiming to detect the pathologies as deviation from the normality by utilizing the unlabeled healthy image data. However, developed UAD models are often trained with an incomplete distribution of healthy anatomies and have difficulties in preserving anatomical constraints. This work intends to, first, propose a robust inpainting model to learn the details of healthy anatomies and reconstruct high-resolution images by preserving anatomical constraints. Second, we propose an autoinpainting pipeline to automatically detect tumors, replace their appearance with the learned healthy anatomies, and based on that segment the tumoral volumes in a purely unsupervised fashion. Three imaging datasets, including PET, CT, and PET-CT scans of lung tumors and head and neck tumors, are studied as benchmarks for evaluation. Experimental results demonstrate the significant superiority of the proposed method over a wide range of state-of-the-art UAD methods. Moreover, the unsupervised method we propose produces comparable results to a robust supervised segmentation method when applied to multimodal images.

The emergence of groundbreaking large language models capable of performing complex reasoning tasks holds significant promise for addressing various scientific challenges, including those arising in complex clinical scenarios. To enable their safe and effective deployment in real-world healthcare settings, it is urgently necessary to benchmark the diagnostic capabilities of current models systematically. Given the limitations of existing medical benchmarks in evaluating advanced diagnostic reasoning, we present DiagnosisArena, a comprehensive and challenging benchmark designed to rigorously assess professional-level diagnostic competence. DiagnosisArena consists of 1,113 pairs of segmented patient cases and corresponding diagnoses, spanning 28 medical specialties, deriving from clinical case reports published in 10 top-tier medical journals. The benchmark is developed through a meticulous construction pipeline, involving multiple rounds of screening and review by both AI systems and human experts, with thorough checks conducted to prevent data leakage. Our study reveals that even the most advanced reasoning models, o3-mini, o1, and DeepSeek-R1, achieve only 45.82%, 31.09%, and 17.79% accuracy, respectively. This finding highlights a significant generalization bottleneck in current large language models when faced with clinical diagnostic reasoning challenges. Through DiagnosisArena, we aim to drive further advancements in AIs diagnostic reasoning capabilities, enabling more effective solutions for real-world clinical diagnostic challenges. We provide the benchmark and evaluation tools for further research and development https://github.com/SPIRAL-MED/DiagnosisArena.

Complex prediction models such as deep learning are the output from fitting machine learning, neural networks, or AI models to a set of training data. These are now standard tools in science. A key challenge with the current generation of models is that they are highly parameterized, which makes describing and interpreting the prediction strategies difficult. We use topological data analysis to transform these complex prediction models into pictures representing a topological view. The result is a map of the predictions that enables inspection. The methods scale up to large datasets across different domains and enable us to detect labeling errors in training data, understand generalization in image classification, and inspect predictions of likely pathogenic mutations in the BRCA1 gene.

Immunohistochemical (IHC) staining highlights the molecular information critical to diagnostics in tissue samples. However, compared to H&E staining, IHC staining can be much more expensive in terms of both labor and the laboratory equipment required. This motivates recent research that demonstrates that the correlations between the morphological information present in the H&E-stained slides and the molecular information in the IHC-stained slides can be used for H&E-to-IHC stain translation. However, due to a lack of pixel-perfect H&E-IHC groundtruth pairs, most existing methods have resorted to relying on expert annotations. To remedy this situation, we present a new loss function, Adaptive Supervised PatchNCE (ASP), to directly deal with the input to target inconsistencies in a proposed H&E-to-IHC image-to-image translation framework. The ASP loss is built upon a patch-based contrastive learning criterion, named Supervised PatchNCE (SP), and augments it further with weight scheduling to mitigate the negative impact of noisy supervision. Lastly, we introduce the Multi-IHC Stain Translation (MIST) dataset, which contains aligned H&E-IHC patches for 4 different IHC stains critical to breast cancer diagnosis. In our experiment, we demonstrate that our proposed method outperforms existing image-to-image translation methods for stain translation to multiple IHC stains. All of our code and datasets are available at https://github.com/lifangda01/AdaptiveSupervisedPatchNCE.

In recent years, the integration of advanced imaging techniques and deep learning methods has significantly advanced computer-aided diagnosis (CAD) systems for breast cancer detection and classification. Transformers, which have shown great promise in computer vision, are now being applied to medical image analysis. However, their application to histopathological images presents challenges due to the need for extensive manual annotations of whole-slide images (WSIs), as these models require large amounts of data to work effectively, which is costly and time-consuming. Furthermore, the quadratic computational cost of Vision Transformers (ViTs) is particularly prohibitive for large, high-resolution histopathological images, especially on edge devices with limited computational resources. In this study, we introduce a novel lightweight breast cancer classification approach using transformers that operates effectively without large datasets. By incorporating parallel processing pathways for Discrete Cosine Transform (DCT) Attention and MobileConv, we convert image data from the spatial domain to the frequency domain to utilize the benefits such as filtering out high frequencies in the image, which reduces computational cost. This demonstrates the potential of our approach to improve breast cancer classification in histopathological images, offering a more efficient solution with reduced reliance on extensive annotated datasets. Our proposed model achieves an accuracy of 96.00% pm 0.48% for binary classification and 87.85% pm 0.93% for multiclass classification, which is comparable to state-of-the-art models while significantly reducing computational costs. This demonstrates the potential of our approach to improve breast cancer classification in histopathological images, offering a more efficient solution with reduced reliance on extensive annotated datasets.