Accurate gland segmentation in histopathology images is essential for cancer diagnosis and prognosis. However, significant variability in Hematoxylin and Eosin (H&E) staining and tissue morphology, combined with limited annotated data, poses major challenges for automated segmentation. To address this, we propose Color-Structure Dual-Student (CSDS), a novel semi-supervised segmentation framework designed to learn disentangled representations of stain appearance and tissue structure. CSDS comprises two specialized student networks: one trained on stain-augmented inputs to model chromatic variation, and the other on structure-augmented inputs to capture morphological cues. A shared teacher network, updated via Exponential Moving Average (EMA), supervises both students through pseudo-labels. To further improve label reliability, we introduce stain-aware and structure-aware uncertainty estimation modules that adaptively modulate the contribution of each student during training. Experiments on the GlaS and CRAG datasets show that CSDS achieves state-of-the-art performance in low-label settings, with Dice score improvements of up to 1.2% on GlaS and 0.7% on CRAG at 5% labeled data, and 0.7% and 1.4% at 10%. Our code and pre-trained models are available at https://github.com/hieuphamha19/CSDS.
Multiple instance learning (MIL) has shown significant promise in histopathology whole slide image (WSI) analysis for cancer diagnosis and prognosis. However, the inherent spatial heterogeneity of WSIs presents critical challenges, as morphologically similar tissue types are often dispersed across distant anatomical regions. Conventional MIL methods struggle to model these scattered tissue distributions and capture cross-regional spatial interactions effectively. To address these limitations, we propose a novel Multiple instance learning framework with Context-Aware Clustering (MiCo), designed to enhance cross-regional intra-tissue correlations and strengthen inter-tissue semantic associations in WSIs. MiCo begins by clustering instances to distill discriminative morphological patterns, with cluster centroids serving as semantic anchors. To enhance cross-regional intra-tissue correlations, MiCo employs a Cluster Route module, which dynamically links instances of the same tissue type across distant regions via feature similarity. These semantic anchors act as contextual hubs, propagating semantic relationships to refine instance-level representations. To eliminate semantic fragmentation and strengthen inter-tissue semantic associations, MiCo integrates a Cluster Reducer module, which consolidates redundant anchors while enhancing information exchange between distinct semantic groups. Extensive experiments on two challenging tasks across nine large-scale public cancer datasets demonstrate the effectiveness of MiCo, showcasing its superiority over state-of-the-art methods. The code is available at https://github.com/junjianli106/MiCo.
Pre-trained encoders for offline feature extraction followed by multiple instance learning (MIL) aggregators have become the dominant paradigm in computational pathology (CPath), benefiting cancer diagnosis and prognosis. However, performance limitations arise from the absence of encoder fine-tuning for downstream tasks and disjoint optimization with MIL. While slide-level supervised end-to-end (E2E) learning is an intuitive solution to this issue, it faces challenges such as high computational demands and suboptimal results. These limitations motivate us to revisit E2E learning. We argue that prior work neglects inherent E2E optimization challenges, leading to performance disparities compared to traditional two-stage methods. In this paper, we pioneer the elucidation of optimization challenge caused by sparse-attention MIL and propose a novel MIL called ABMILX. It mitigates this problem through global correlation-based attention refinement and multi-head mechanisms. With the efficient multi-scale random patch sampling strategy, an E2E trained ResNet with ABMILX surpasses SOTA foundation models under the two-stage paradigm across multiple challenging benchmarks, while remaining computationally efficient (<10 RTX3090 hours). We show the potential of E2E learning in CPath and calls for greater research focus in this area. The code is https://github.com/DearCaat/E2E-WSI-ABMILX.
A cardiac digital twin is a virtual replica of a patient's heart for screening, diagnosis, prognosis, risk assessment, and treatment planning of cardiovascular diseases. This requires an anatomically accurate patient-specific 3D structural representation of the heart, suitable for electro-mechanical simulations or study of disease mechanisms. However, generation of cardiac digital twins at scale is demanding and there are no public repositories of models across demographic groups. We describe an automatic open-source pipeline for creating patient-specific left and right ventricular meshes from cardiovascular magnetic resonance images, its application to a large cohort of ~55000 participants from UK Biobank, and the construction of the most comprehensive cohort of adult heart models to date, comprising 1423 representative meshes across sex (male, female), body mass index (range: 16 - 42 kg/m$^2$) and age (range: 49 - 80 years). Our code is available at https://github.com/cdttk/biv-volumetric-meshing/tree/plos2025 , and pre-trained networks, representative volumetric meshes with fibers and UVCs will be made available soon.
Introduction: Timely identification of intracranial hemorrhage (ICH) subtypes on non-contrast computed tomography is critical for prognosis prediction and therapeutic decision-making, yet remains challenging due to low contrast and blurring boundaries. This study evaluates the performance of zero-shot multi-modal large language models (MLLMs) compared to traditional deep learning methods in ICH binary classification and subtyping. Methods: We utilized a dataset provided by RSNA, comprising 192 NCCT volumes. The study compares various MLLMs, including GPT-4o, Gemini 2.0 Flash, and Claude 3.5 Sonnet V2, with conventional deep learning models, including ResNet50 and Vision Transformer. Carefully crafted prompts were used to guide MLLMs in tasks such as ICH presence, subtype classification, localization, and volume estimation. Results: The results indicate that in the ICH binary classification task, traditional deep learning models outperform MLLMs comprehensively. For subtype classification, MLLMs also exhibit inferior performance compared to traditional deep learning models, with Gemini 2.0 Flash achieving an macro-averaged precision of 0.41 and a macro-averaged F1 score of 0.31. Conclusion: While MLLMs excel in interactive capabilities, their overall accuracy in ICH subtyping is inferior to deep networks. However, MLLMs enhance interpretability through language interactions, indicating potential in medical imaging analysis. Future efforts will focus on model refinement and developing more precise MLLMs to improve performance in three-dimensional medical image processing.
Histopathology evaluation of tissue specimens through microscopic examination is essential for accurate disease diagnosis and prognosis. However, traditional manual analysis by specially trained pathologists is time-consuming, labor-intensive, cost-inefficient, and prone to inter-rater variability, potentially affecting diagnostic consistency and accuracy. As digital pathology images continue to proliferate, there is a pressing need for automated analysis to address these challenges. Recent advancements in artificial intelligence-based tools such as machine learning (ML) models, have significantly enhanced the precision and efficiency of analyzing histopathological slides. However, despite their impressive performance, ML models are invariant only to translation, lacking invariance to rotation and reflection. This limitation restricts their ability to generalize effectively, particularly in histopathology, where images intrinsically lack meaningful orientation. In this study, we develop robust, equivariant histopathological biomarkers through a novel symmetric convolutional kernel via unsupervised segmentation. The approach is validated using prostate tissue micro-array (TMA) images from 50 patients in the Gleason 2019 Challenge public dataset. The biomarkers extracted through this approach demonstrate enhanced robustness and generalizability against rotation compared to models using standard convolution kernels, holding promise for enhancing the accuracy, consistency, and robustness of ML models in digital pathology. Ultimately, this work aims to improve diagnostic and prognostic capabilities of histopathology beyond prostate cancer through equivariant imaging.
Neuroblastoma, adrenal-derived, is among the most common pediatric solid malignancies, characterized by significant clinical heterogeneity. Timely and accurate pathological diagnosis from hematoxylin and eosin-stained whole-slide images is critical for patient prognosis. However, current diagnostic practices primarily rely on subjective manual examination by pathologists, leading to inconsistent accuracy. Existing automated whole-slide image classification methods encounter challenges such as poor interpretability, limited feature extraction capabilities, and high computational costs, restricting their practical clinical deployment. To overcome these limitations, we propose CMSwinKAN, a contrastive-learning-based multi-scale feature fusion model tailored for pathological image classification, which enhances the Swin Transformer architecture by integrating a Kernel Activation Network within its multilayer perceptron and classification head modules, significantly improving both interpretability and accuracy. By fusing multi-scale features and leveraging contrastive learning strategies, CMSwinKAN mimics clinicians' comprehensive approach, effectively capturing global and local tissue characteristics. Additionally, we introduce a heuristic soft voting mechanism guided by clinical insights to bridge patch-level predictions to whole-slide image-level classifications seamlessly. We verified the CMSwinKAN on the publicly available BreakHis dataset and the PpNTs dataset, which was established by our hospital. Results demonstrate that CMSwinKAN performs better than existing state-of-the-art pathology-specific models pre-trained on large datasets. Our source code is available at https://github.com/JSLiam94/CMSwinKAN.
Cancer remains a leading global health challenge and a major cause of mortality. This study leverages machine learning (ML) to predict the survivability of cancer patients with metastatic patterns using the comprehensive MSK-MET dataset, which includes genomic and clinical data from 25,775 patients across 27 cancer types. We evaluated five ML models-XGBoost, Na\"ive Bayes, Decision Tree, Logistic Regression, and Random Fores using hyperparameter tuning and grid search. XGBoost emerged as the best performer with an area under the curve (AUC) of 0.82. To enhance model interpretability, SHapley Additive exPlanations (SHAP) were applied, revealing key predictors such as metastatic site count, tumor mutation burden, fraction of genome altered, and organ-specific metastases. Further survival analysis using Kaplan-Meier curves, Cox Proportional Hazards models, and XGBoost Survival Analysis identified significant predictors of patient outcomes, offering actionable insights for clinicians. These findings could aid in personalized prognosis and treatment planning, ultimately improving patient care.
An important goal in cancer research is the survival prognosis of a patient based on a minimal panel of genomic and molecular markers such as genes or proteins. Purely data-driven models without any biological knowledge can produce non-interpretable results. We propose a penalized semiparametric Bayesian Cox model with graph-structured selection priors for sparse identification of multi-omics features by making use of a biologically meaningful graph via a Markov random field (MRF) prior to capturing known relationships between multi-omics features. Since the fixed graph in the MRF prior is for the prior probability distribution, it is not a hard constraint to determine variable selection, so the proposed model can verify known information and has the potential to identify new and novel biomarkers for drawing new biological knowledge. Our simulation results show that the proposed Bayesian Cox model with graph-based prior knowledge results in more trustable and stable variable selection and non-inferior survival prediction, compared to methods modeling the covariates independently without any prior knowledge. The results also indicate that the performance of the proposed model is robust to a partially correct graph in the MRF prior, meaning that in a real setting where not all the true network information between covariates is known, the graph can still be useful. The proposed model is applied to the primary invasive breast cancer patients data in The Cancer Genome Atlas project.
Knowledge of the force time history of a structure is essential to assess its behaviour, ensure safety and maintain reliability. However, direct measurement of external forces is often challenging due to sensor limitations, unknown force characteristics, or inaccessible load points. This paper presents an efficient dynamic load reconstruction method using physics-informed Gaussian processes (GP) based on frequency-sparse Fourier basis functions. The GP's covariance matrices are built using the description of the system dynamics, and the model is trained using structural response measurements. This provides support and interpretability to the machine learning model, in contrast to purely data-driven methods. In addition, the model filters out irrelevant components in the Fourier basis function by leveraging the sparsity of structural responses in the frequency domain, thereby reducing computational complexity during optimization. The trained model for structural responses is then integrated with the differential equation for a harmonic oscillator, creating a probabilistic dynamic load model that predicts load patterns without requiring force data during training. The model's effectiveness is validated through two case studies: a numerical model of a wind-excited 76-story building and an experiment using a physical scale model of the Lilleb{\ae}lt Bridge in Denmark, excited by a servo motor. For both cases, validation of the reconstructed forces is provided using comparison metrics for several signal properties. The developed model holds potential for applications in structural health monitoring, damage prognosis, and load model validation.
Molecular subtyping of breast cancer is crucial for personalized treatment and prognosis. Traditional classification approaches rely on either histopathological images or gene expression profiling, limiting their predictive power. In this study, we propose a deep multimodal learning framework that integrates histopathological images and gene expression data to classify breast cancer into BRCA.Luminal and BRCA.Basal / Her2 subtypes. Our approach employs a ResNet-50 model for image feature extraction and fully connected layers for gene expression processing, with a cross-attention fusion mechanism to enhance modality interaction. We conduct extensive experiments using five-fold cross-validation, demonstrating that our multimodal integration outperforms unimodal approaches in terms of classification accuracy, precision-recall AUC, and F1-score. Our findings highlight the potential of deep learning for robust and interpretable breast cancer subtype classification, paving the way for improved clinical decision-making.
Cancer survival prediction from whole slide images (WSIs) is a challenging task in computational pathology due to the large size, irregular shape, and high granularity of the WSIs. These characteristics make it difficult to capture the full spectrum of patterns, from subtle cellular abnormalities to complex tissue interactions, which are crucial for accurate prognosis. To address this, we propose CrossFusion, a novel multi-scale feature integration framework that extracts and fuses information from patches across different magnification levels. By effectively modeling both scale-specific patterns and their interactions, CrossFusion generates a rich feature set that enhances survival prediction accuracy. We validate our approach across six cancer types from public datasets, demonstrating significant improvements over existing state-of-the-art methods. Moreover, when coupled with domain-specific feature extraction backbones, our method shows further gains in prognostic performance compared to general-purpose backbones. The source code is available at: https://github.com/RustinS/CrossFusion
Accurate lymph node (LN) segmentation is critical in radiotherapy treatment and prognosis analysis, but is limited by the need for large annotated datasets. While deep learning-based segmentation foundation models show potential in developing high-performing models with fewer samples, their medical adaptation faces LN domain-specific prior deficiencies and inefficient few-shot fine-tuning for complex clinical practices, highlighting the necessity of an LN segmentation foundation model. In this work, we annotated 36,106 visible LNs from 3,346 publicly available head-and-neck CT scans to establish a robust LN segmentation model (nnUNetv2). Building on this, we propose Dynamic Gradient Sparsification Training (DGST), a few-shot fine-tuning approach that preserves foundational knowledge while dynamically updating the most critical parameters of the LN segmentation model with few annotations. We validate it on two publicly available LN segmentation datasets: SegRap2023 and LNQ2023. The results show that DGST outperforms existing few-shot fine-tuning methods, achieving satisfactory performance with limited labeled data. We release the dataset, models and all implementations to facilitate relevant research: https://github.com/Zihaoluoh/LN-Seg-FM.
Large Language Models (LLMs) have shown significant promise across various natural language processing tasks. However, their application in the field of pathology, particularly for extracting meaningful insights from unstructured medical texts such as pathology reports, remains underexplored and not well quantified. In this project, we leverage state-of-the-art language models, including the GPT family, Mistral models, and the open-source Llama models, to evaluate their performance in comprehensively analyzing pathology reports. Specifically, we assess their performance in cancer type identification, AJCC stage determination, and prognosis assessment, encompassing both information extraction and higher-order reasoning tasks. Based on a detailed analysis of their performance metrics in a zero-shot setting, we developed two instruction-tuned models: Path-llama3.1-8B and Path-GPT-4o-mini-FT. These models demonstrated superior performance in zero-shot cancer type identification, staging, and prognosis assessment compared to the other models evaluated.
Cancers are characterized by remarkable heterogeneity and diverse prognosis. Accurate cancer classification is essential for patient stratification and clinical decision-making. Although digital pathology has been advancing cancer diagnosis and prognosis, the paradigm in cancer pathology has shifted from purely relying on histology features to incorporating molecular markers. There is an urgent need for digital pathology methods to meet the needs of the new paradigm. We introduce a novel digital pathology approach to jointly predict molecular markers and histology features and model their interactions for cancer classification. Firstly, to mitigate the challenge of cross-magnification information propagation, we propose a multi-scale disentangling module, enabling the extraction of multi-scale features from high-magnification (cellular-level) to low-magnification (tissue-level) whole slide images. Further, based on the multi-scale features, we propose an attention-based hierarchical multi-task multi-instance learning framework to simultaneously predict histology and molecular markers. Moreover, we propose a co-occurrence probability-based label correlation graph network to model the co-occurrence of molecular markers. Lastly, we design a cross-modal interaction module with the dynamic confidence constrain loss and a cross-modal gradient modulation strategy, to model the interactions of histology and molecular markers. Our experiments demonstrate that our method outperforms other state-of-the-art methods in classifying glioma, histology features and molecular markers. Our method promises to promote precise oncology with the potential to advance biomedical research and clinical applications. The code is available at https://github.com/LHY1007/M3C2
Precise segmentation and classification of cell instances are vital for analyzing the tissue microenvironment in histology images, supporting medical diagnosis, prognosis, treatment planning, and studies of brain cytoarchitecture. However, the creation of high-quality annotated datasets for training remains a major challenge. This study introduces a novel single-stage approach (HistoSmith) for generating image-label pairs to augment histology datasets. Unlike state-of-the-art methods that utilize diffusion models with separate components for label and image generation, our approach employs a latent diffusion model to learn the joint distribution of cellular layouts, classification masks, and histology images. This model enables tailored data generation by conditioning on user-defined parameters such as cell types, quantities, and tissue types. Trained on the Conic H&E histopathology dataset and the Nissl-stained CytoDArk0 dataset, the model generates realistic and diverse labeled samples. Experimental results demonstrate improvements in cell instance segmentation and classification, particularly for underrepresented cell types like neutrophils in the Conic dataset. These findings underscore the potential of our approach to address data scarcity challenges.
Emerging research has highlighted that artificial intelligence based multimodal fusion of digital pathology and transcriptomic features can improve cancer diagnosis (grading/subtyping) and prognosis (survival risk) prediction. However, such direct fusion for joint decision is impractical in real clinical settings, where histopathology is still the gold standard for diagnosis and transcriptomic tests are rarely requested, at least in the public healthcare system. With our novel diffusion based crossmodal generative AI model PathoGen, we show that genomic expressions synthesized from digital histopathology jointly predicts cancer grading and patient survival risk with high accuracy (state-of-the-art performance), certainty (through conformal coverage guarantee) and interpretability (through distributed attention maps). PathoGen code is available for open use by the research community through GitHub at https://github.com/Samiran-Dey/PathoGen.
Cancer diagnosis and prognosis primarily depend on clinical parameters such as age and tumor grade, and are increasingly complemented by molecular data, such as gene expression, from tumor sequencing. However, sequencing is costly and delays oncology workflows. Recent advances in Deep Learning allow to predict molecular information from morphological features within Whole Slide Images (WSIs), offering a cost-effective proxy of the molecular markers. While promising, current methods lack the robustness to fully replace direct sequencing. Here we aim to improve existing methods by introducing a model-agnostic framework that allows to inject prior knowledge on gene-gene interactions into Deep Learning architectures, thereby increasing accuracy and robustness. We design the framework to be generic and flexibly adaptable to a wide range of architectures. In a case study on breast cancer, our strategy leads to an average increase of 983 significant genes (out of 25,761) across all 18 experiments, with 14 generalizing to an increase on an independent dataset. Our findings reveal a high potential for injection of prior knowledge to increase gene expression prediction performance from WSIs across a wide range of architectures.
Survival prognosis is crucial for medical informatics. Practitioners often confront small-sized clinical data, especially cancer patient cases, which can be insufficient to induce useful patterns for survival predictions. This study deals with small sample survival analysis by leveraging transfer learning, a useful machine learning technique that can enhance the target analysis with related knowledge pre-learned from other data. We propose and develop various transfer learning methods designed for common survival models. For parametric models such as DeepSurv, Cox-CC (Cox-based neural networks), and DeepHit (end-to-end deep learning model), we apply standard transfer learning techniques like pretraining and fine-tuning. For non-parametric models such as Random Survival Forest, we propose a new transfer survival forest (TSF) model that transfers tree structures from source tasks and fine-tunes them with target data. We evaluated the transfer learning methods on colorectal cancer (CRC) prognosis. The source data are 27,379 SEER CRC stage I patients, and the target data are 728 CRC stage I patients from the West China Hospital. When enhanced by transfer learning, Cox-CC's $C^{td}$ value was boosted from 0.7868 to 0.8111, DeepHit's from 0.8085 to 0.8135, DeepSurv's from 0.7722 to 0.8043, and RSF's from 0.7940 to 0.8297 (the highest performance). All models trained with data as small as 50 demonstrated even more significant improvement. Conclusions: Therefore, the current survival models used for cancer prognosis can be enhanced and improved by properly designed transfer learning techniques. The source code used in this study is available at https://github.com/YonghaoZhao722/TSF.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with lung metastases being the most common site of distant spread and significantly worsening prognosis. Despite the growing availability of clinical and demographic data, predictive models for lung metastasis in HCC remain limited in scope and clinical applicability. In this study, we develop and validate an end-to-end machine learning pipeline using data from the Surveillance, Epidemiology, and End Results (SEER) database. We evaluated three machine learning models (Random Forest, XGBoost, and Logistic Regression) alongside a multilayer perceptron (MLP) neural network. Our models achieved high AUROC values and recall, with the Random Forest and MLP models demonstrating the best overall performance (AUROC = 0.82). However, the low precision across models highlights the challenges of accurately predicting positive cases. To address these limitations, we developed a custom loss function incorporating recall optimization, enabling the MLP model to achieve the highest sensitivity. An ensemble approach further improved overall recall by leveraging the strengths of individual models. Feature importance analysis revealed key predictors such as surgery status, tumor staging, and follow up duration, emphasizing the relevance of clinical interventions and disease progression in metastasis prediction. While this study demonstrates the potential of machine learning for identifying high-risk patients, limitations include reliance on imbalanced datasets, incomplete feature annotations, and the low precision of predictions. Future work should leverage the expanding SEER dataset, improve data imputation techniques, and explore advanced pre-trained models to enhance predictive accuracy and clinical utility.