A Pathology Foundation Model for Gastric Cancer with Real-World Validation

Gastric cancer remains a major cause of cancer mortality, yet its histological and molecular heterogeneity complicates diagnosis and risk stratification. General-purpose pathology foundation models (PFMs) often plateau on fine-grained endpoints central to gastric cancer care, and few have undergone rigorous prospective validation or clinical reader studies. We present GRACE, a Gastric-specific foundation model for Real-world Assessment and Clinical dEcision support. GRACE was developed from multicenter gastric pathology datasets totaling 48,364 primarily HE-stained whole-slide images from 37,493 patients. When evaluated on 28 clinically relevant tasks, GRACE consistently outperformed representative pancancer PFMs, achieving a macro-AUC of 0.9188, with strong performance for precancerous lesion diagnosis (macro-AUC 0.9322), tumor histopathological assessment (macro-AUC 0.9119), molecular profiling (macro-AUC 0.8682), and prognostic prediction. Beyond benchmarking, GRACE's translational value was substantiated through a rigorous evidence chain. Under safety-gated criteria requiring 100% NPV for rule-out and 100% PPV for rule-in, GRACE streamlined review for up to 69.6% of malignancy-diagnosis cases and triaged 46.8% of MMR-IHC follow-up requests. This translational feasibility was further strengthened by a randomized crossover reader study of pathologist-AI collaboration. With GRACE assistance, diagnostic accuracy improved from 82.0% to 89.9%, yielding nearly twofold higher adjusted odds of a correct diagnosis (OR 1.987) alongside concurrent gains in sensitivity and specificity. AI assistance also reduced diagnostic time by 14.9%, elevated diagnostic confidence by 9.0%, and markedly improved inter-rater agreement. When calibrated to maintain non-inferior performance to senior pathologists, the AI-assisted workflow could triage 60.7% of atrophy and 82.7% of intestinal metaplasia cases.

Spatial Transcriptomics-Guided Alignment Enhances Molecular Profiling in Pathology Foundation Model

Comprehensive molecular profiling is essential for modern precision oncology but remains hindered by prohibitive costs, specimen exhaustion, and protracted turnaround times. While pathology foundation models (PFMs) have demonstrated potential for inferring molecular phenotypes from routine hematoxylin and eosin (H&E) whole-slide images (WSIs), current architectures primarily rely on vision-centric self-supervised learning or vision-language alignment, lacking the spatially resolved molecular supervision required to connect subtle morphological features with underlying genomic alterations. Spatial transcriptomics (ST) emerges as a transformative technology that enables transcriptomic quantification within intact tissue sections, thereby preserving the precise spatial link between histology and molecular profiles. In this study, we present a Spatial Transcriptomics-guided Alignment framework for Molecular Profiling (STAMP), which endows PFMs with intrinsic molecular awareness. To support this paradigm, we curated HumanST-1k, a human ST dataset spanning diverse anatomical organs and sequencing platforms. This atlas yields 1.8 million pairs of H&E patches and corresponding transcriptomic profiles, providing a corpus that links histological structures with their molecular states. To mitigate the technical noise inherent to raw transcriptomics, STAMP applies a pathway-informed alignment strategy that aggregates transcriptomic data into biologically functional pathways, which are subsequently integrated into PFMs via parameter-efficient fine-tuning. This alignment enriches the representation space of PFMs and unlocks their capacity to resolve sub-visual molecular signatures. The clinical utility of these augmented representations was validated through a multi-tier evaluation framework.

A Clinically Validated Foundation Model for Comprehensive Lung Pathology Interpretation

Pathological assessment guides lung cancer diagnosis, treatment selection, and prognostic evaluation, yet current CPath approaches rely on task-specific models for isolated objectives. Although pan-cancer foundation models offer versatility, they lack subspecialty-level depth and have not been evaluated across clinical workflows or prospectively validated in real-world settings. We introduce PulmoFoundation, a multi-center, prospectively validated, randomized controlled trial (RCT)-evaluated foundation model for comprehensive lung pathology assessment across pre-operative, intra-operative, and post-operative care. Built upon Virchow2 via subspecialty-specific pretraining using ~40,000 diagnostic H&E-stained whole-slide images (WSIs), PulmoFoundation was systematically evaluated on ~26,000 WSIs across 32 clinically relevant tasks. In addition to accurately predicting molecular markers and patient survival, our model achieves clinical-grade performance in core diagnostic tasks across biopsy, frozen section, and surgical resection slides. In a registered prospective study of 1,357 patients across 11 diagnostic tasks, our model achieved an average AUC of 92.3%. Using pre-specified triage thresholds, PulmoFoundation could reduce additional second-review burden for 68.8% of biopsies and 83.0% of frozen sections, and defer 44.5% of IHC stain orders, with PPVs of 1.0, 0.991, and 0.966. Beyond prospective validation, we conducted a crossover RCT with eight pathologists, in which AI assistance improved diagnostic accuracy across 4,928 case-reader pairs (91.7% w/ AI vs. 83.8% w/o AI). AI assistance also reduced median diagnostic time by 19.6%, increased diagnostic confidence by 8.7%, and improved inter-rater agreement from moderate (kappa = 0.56) to substantial (kappa = 0.76). Together, these evaluations support PulmoFoundation as a clinically validated decision-support system for lung pathology.

A Decade-Scale Benchmark Evaluating LLMs' Clinical Practice Guidelines Detection and Adherence in Multi-turn Conversations

Clinical practice guidelines (CPGs) play a pivotal role in ensuring evidence-based decision-making and improving patient outcomes. While Large Language Models (LLMs) are increasingly deployed in healthcare scenarios, it is unclear to which extend LLMs could identify and adhere to CPGs during conversations. To address this gap, we introduce CPGBench, an automated framework benchmarking the clinical guideline detection and adherence capabilities of LLMs in multi-turn conversations. We collect 3,418 CPG documents from 9 countries/regions and 2 international organizations published in the last decade spanning across 24 specialties. From these documents, we extract 32,155 clinical recommendations with corresponding publication institute, date, country, specialty, recommendation strength, evidence level, etc. One multi-turn conversation is generated for each recommendation accordingly to evaluate the detection and adherence capabilities of 8 leading LLMs. We find that the 71.1%-89.6% recommendations can be correctly detected, while only 3.6%-29.7% corresponding titles can be correctly referenced, revealing the gap between knowing the guideline contents and where they come from. The adherence rates range from 21.8% to 63.2% in different models, indicating a large gap between knowing the guidelines and being able to apply them. To confirm the validity of our automatic analysis, we further conduct a comprehensive human evaluation involving 56 clinicians from different specialties. To our knowledge, CPGBench is the first benchmark systematically revealing which clinical recommendations LLMs fail to detect or adhere to during conversations. Given that each clinical recommendation may affect a large population and that clinical applications are inherently safety critical, addressing these gaps is crucial for the safe and responsible deployment of LLMs in real world clinical practice.

A Deployment-Friendly Foundational Framework for Efficient Computational Pathology

Pathology foundation models (PFMs) have enabled robust generalization in computational pathology through large-scale datasets and expansive architectures, but their substantial computational cost, particularly for gigapixel whole slide images, limits clinical accessibility and scalability. Here, we present LitePath, a deployment-friendly foundational framework designed to mitigate model over-parameterization and patch level redundancy. LitePath integrates LiteFM, a compact model distilled from three large PFMs (Virchow2, H-Optimus-1 and UNI2) using 190 million patches, and the Adaptive Patch Selector (APS), a lightweight component for task-specific patch selection. The framework reduces model parameters by 28x and lowers FLOPs by 403.5x relative to Virchow2, enabling deployment on low-power edge hardware such as the NVIDIA Jetson Orin Nano Super. On this device, LitePath processes 208 slides per hour, 104.5x faster than Virchow2, and consumes 0.36 kWh per 3,000 slides, 171x lower than Virchow2 on an RTX3090 GPU. We validated accuracy using 37 cohorts across four organs and 26 tasks (26 internal, 9 external, and 2 prospective), comprising 15,672 slides from 9,808 patients disjoint from the pretraining data. LitePath ranks second among 19 evaluated models and outperforms larger models including H-Optimus-1, mSTAR, UNI2 and GPFM, while retaining 99.71% of the AUC of Virchow2 on average. To quantify the balance between accuracy and efficiency, we propose the Deployability Score (D-Score), defined as the weighted geometric mean of normalized AUC and normalized FLOP, where LitePath achieves the highest value, surpassing Virchow2 by 10.64%. These results demonstrate that LitePath enables rapid, cost-effective and energy-efficient pathology image analysis on accessible hardware while maintaining accuracy comparable to state-of-the-art PFMs and reducing the carbon footprint of AI deployment.

MambaMIL+: Modeling Long-Term Contextual Patterns for Gigapixel Whole Slide Image

Whole-slide images (WSIs) are an important data modality in computational pathology, yet their gigapixel resolution and lack of fine-grained annotations challenge conventional deep learning models. Multiple instance learning (MIL) offers a solution by treating each WSI as a bag of patch-level instances, but effectively modeling ultra-long sequences with rich spatial context remains difficult. Recently, Mamba has emerged as a promising alternative for long sequence learning, scaling linearly to thousands of tokens. However, despite its efficiency, it still suffers from limited spatial context modeling and memory decay, constraining its effectiveness to WSI analysis. To address these limitations, we propose MambaMIL+, a new MIL framework that explicitly integrates spatial context while maintaining long-range dependency modeling without memory forgetting. Specifically, MambaMIL+ introduces 1) overlapping scanning, which restructures the patch sequence to embed spatial continuity and instance correlations; 2) a selective stripe position encoder (S2PE) that encodes positional information while mitigating the biases of fixed scanning orders; and 3) a contextual token selection (CTS) mechanism, which leverages supervisory knowledge to dynamically enlarge the contextual memory for stable long-range modeling. Extensive experiments on 20 benchmarks across diagnostic classification, molecular prediction, and survival analysis demonstrate that MambaMIL+ consistently achieves state-of-the-art performance under three feature extractors (ResNet-50, PLIP, and CONCH), highlighting its effectiveness and robustness for large-scale computational pathology

LLM-driven Knowledge Enhancement for Multimodal Cancer Survival Prediction

Current multimodal survival prediction methods typically rely on pathology images (WSIs) and genomic data, both of which are high-dimensional and redundant, making it difficult to extract discriminative features from them and align different modalities. Moreover, using a simple survival follow-up label is insufficient to supervise such a complex task. To address these challenges, we propose KEMM, an LLM-driven Knowledge-Enhanced Multimodal Model for cancer survival prediction, which integrates expert reports and prognostic background knowledge. 1) Expert reports, provided by pathologists on a case-by-case basis and refined by large language model (LLM), offer succinct and clinically focused diagnostic statements. This information may typically suggest different survival outcomes. 2) Prognostic background knowledge (PBK), generated concisely by LLM, provides valuable prognostic background knowledge on different cancer types, which also enhances survival prediction. To leverage these knowledge, we introduce the knowledge-enhanced cross-modal (KECM) attention module. KECM can effectively guide the network to focus on discriminative and survival-relevant features from highly redundant modalities. Extensive experiments on five datasets demonstrate that KEMM achieves state-of-the-art performance. The code will be released upon acceptance.

A Clinical-grade Universal Foundation Model for Intraoperative Pathology

Intraoperative pathology is pivotal to precision surgery, yet its clinical impact is constrained by diagnostic complexity and the limited availability of high-quality frozen-section data. While computational pathology has made significant strides, the lack of large-scale, prospective validation has impeded its routine adoption in surgical workflows. Here, we introduce CRISP, a clinical-grade foundation model developed on over 100,000 frozen sections from eight medical centers, specifically designed to provide Clinical-grade Robust Intraoperative Support for Pathology (CRISP). CRISP was comprehensively evaluated on more than 15,000 intraoperative slides across nearly 100 retrospective diagnostic tasks, including benign-malignant discrimination, key intraoperative decision-making, and pan-cancer detection, etc. The model demonstrated robust generalization across diverse institutions, tumor types, and anatomical sites-including previously unseen sites and rare cancers. In a prospective cohort of over 2,000 patients, CRISP sustained high diagnostic accuracy under real-world conditions, directly informing surgical decisions in 92.6% of cases. Human-AI collaboration further reduced diagnostic workload by 35%, avoided 105 ancillary tests and enhanced detection of micrometastases with 87.5% accuracy. Together, these findings position CRISP as a clinical-grade paradigm for AI-driven intraoperative pathology, bridging computational advances with surgical precision and accelerating the translation of artificial intelligence into routine clinical practice.

Generative AI for Misalignment-Resistant Virtual Staining to Accelerate Histopathology Workflows

Accurate histopathological diagnosis often requires multiple differently stained tissue sections, a process that is time-consuming, labor-intensive, and environmentally taxing due to the use of multiple chemical stains. Recently, virtual staining has emerged as a promising alternative that is faster, tissue-conserving, and environmentally friendly. However, existing virtual staining methods face significant challenges in clinical applications, primarily due to their reliance on well-aligned paired data. Obtaining such data is inherently difficult because chemical staining processes can distort tissue structures, and a single tissue section cannot undergo multiple staining procedures without damage or loss of information. As a result, most available virtual staining datasets are either unpaired or roughly paired, making it difficult for existing methods to achieve accurate pixel-level supervision. To address this challenge, we propose a robust virtual staining framework featuring cascaded registration mechanisms to resolve spatial mismatches between generated outputs and their corresponding ground truth. Experimental results demonstrate that our method significantly outperforms state-of-the-art models across five datasets, achieving an average improvement of 3.2% on internal datasets and 10.1% on external datasets. Moreover, in datasets with substantial misalignment, our approach achieves a remarkable 23.8% improvement in peak signal-to-noise ratio compared to baseline models. The exceptional robustness of the proposed method across diverse datasets simplifies the data acquisition process for virtual staining and offers new insights for advancing its development.

A Multimodal Foundation Model to Enhance Generalizability and Data Efficiency for Pan-cancer Prognosis Prediction

Multimodal data provides heterogeneous information for a holistic understanding of the tumor microenvironment. However, existing AI models often struggle to harness the rich information within multimodal data and extract poorly generalizable representations. Here we present MICE (Multimodal data Integration via Collaborative Experts), a multimodal foundation model that effectively integrates pathology images, clinical reports, and genomics data for precise pan-cancer prognosis prediction. Instead of conventional multi-expert modules, MICE employs multiple functionally diverse experts to comprehensively capture both cross-cancer and cancer-specific insights. Leveraging data from 11,799 patients across 30 cancer types, we enhanced MICE's generalizability by coupling contrastive and supervised learning. MICE outperformed both unimodal and state-of-the-art multi-expert-based multimodal models, demonstrating substantial improvements in C-index ranging from 3.8% to 11.2% on internal cohorts and 5.8% to 8.8% on independent cohorts, respectively. Moreover, it exhibited remarkable data efficiency across diverse clinical scenarios. With its enhanced generalizability and data efficiency, MICE establishes an effective and scalable foundation for pan-cancer prognosis prediction, holding strong potential to personalize tailored therapies and improve treatment outcomes.