Low-grade gliomas frequently present IDH1 mutations that define clinically distinct subgroups with specific prognostic and therapeutic implications. This work introduces a Multimodal Oncology Agent (MOA) integrating a histology tool based on the TITAN foundation model for IDH1 mutation prediction in low-grade glioma, combined with reasoning over structured clinical and genomic inputs through PubMed, Google Search, and OncoKB. MOA reports were quantitatively evaluated on 488 patients from the TCGA-LGG cohort against clinical and histology baselines. MOA without the histology tool outperformed the clinical baseline, achieving an F1-score of 0.826 compared to 0.798. When fused with histology features, MOA reached the highest performance with an F1-score of 0.912, exceeding both the histology baseline at 0.894 and the fused histology-clinical baseline at 0.897. These results demonstrate that the proposed agent captures complementary mutation-relevant information enriched through external biomedical sources, enabling accurate IDH1 mutation prediction.

Automated approaches to answer patient-posed health questions are rising, but selecting among systems requires reliable evaluation. The current gold standard for evaluating the free-text artificial intelligence (AI) responses--human expert review--is labor-intensive and slow, limiting scalability. Automated metrics are promising yet variably aligned with human judgments and often context-dependent. To address the feasibility of automating the evaluation of AI responses to hospitalization-related questions posed by patients, we conducted a large systematic study of evaluation approaches. Across 100 patient cases, we collected responses from 28 AI systems (2800 total) and assessed them along three dimensions: whether a system response (1) answers the question, (2) appropriately uses clinical note evidence, and (3) uses general medical knowledge. Using clinician-authored reference answers to anchor metrics, automated rankings closely matched expert ratings. Our findings suggest that carefully designed automated evaluation can scale comparative assessment of AI systems and support patient-clinician communication.

AI has the potential to augment human decision making. However, even high-performing models can produce inaccurate predictions when deployed. These inaccuracies, combined with automation bias, where humans overrely on AI predictions, can result in worse decisions. Selective prediction, in which potentially unreliable model predictions are hidden from users, has been proposed as a solution. This approach assumes that when AI abstains and informs the user so, humans make decisions as they would without AI involvement. To test this assumption, we study the effects of selective prediction on human decisions in a clinical context. We conducted a user study of 259 clinicians tasked with diagnosing and treating hospitalized patients. We compared their baseline performance without any AI involvement to their AI-assisted accuracy with and without selective prediction. Our findings indicate that selective prediction mitigates the negative effects of inaccurate AI in terms of decision accuracy. Compared to no AI assistance, clinician accuracy declined when shown inaccurate AI predictions (66% [95% CI: 56%-75%] vs. 56% [95% CI: 46%-66%]), but recovered under selective prediction (64% [95% CI: 54%-73%]). However, while selective prediction nearly maintains overall accuracy, our results suggest that it alters patterns of mistakes: when informed the AI abstains, clinicians underdiagnose (18% increase in missed diagnoses) and undertreat (35% increase in missed treatments) compared to no AI input at all. Our findings underscore the importance of empirically validating assumptions about how humans engage with AI within human-AI systems.

Clinical trials are crucial for assessing new treatments; however, recruitment challenges - such as limited awareness, complex eligibility criteria, and referral barriers - hinder their success. With the growth of online platforms, patients increasingly turn to social media and health communities for support, research, and advocacy, expanding recruitment pools and established enrollment pathways. Recognizing this potential, we utilized TrialGPT, a framework that leverages a large language model (LLM) as its backbone, to match 50 online patient cases (collected from published case reports and a social media website) to clinical trials and evaluate performance against traditional keyword-based searches. Our results show that TrialGPT outperforms traditional methods by 46% in identifying eligible trials, with each patient, on average, being eligible for around 7 trials. Additionally, our outreach efforts to case authors and trial organizers regarding these patient-trial matches yielded highly positive feedback, which we present from both perspectives.

In this paper we propose an advanced approach to integrating artificial intelligence (AI) into healthcare: autonomous decision support. This approach allows the AI algorithm to act autonomously for a subset of patient cases whilst serving a supportive role in other subsets of patient cases based on defined delegation criteria. By leveraging the complementary strengths of both humans and AI, it aims to deliver greater overall performance than existing human-AI teaming models. It ensures safe handling of patient cases and potentially reduces clinician review time, whilst being mindful of AI tool limitations. After setting the approach within the context of current human-AI teaming models, we outline the delegation criteria and apply them to a specific AI-based tool used in histopathology. The potential impact of the approach and the regulatory requirements for its successful implementation are then discussed.

Recent advancements in reasoning-enhanced large language models (LLMs), such as DeepSeek-R1 and OpenAI-o3, have demonstrated significant progress. However, their application in professional medical contexts remains underexplored, particularly in evaluating the quality of their reasoning processes alongside final outputs. Here, we introduce MedR-Bench, a benchmarking dataset of 1,453 structured patient cases, annotated with reasoning references derived from clinical case reports. Spanning 13 body systems and 10 specialties, it includes both common and rare diseases. To comprehensively evaluate LLM performance, we propose a framework encompassing three critical examination recommendation, diagnostic decision-making, and treatment planning, simulating the entire patient care journey. To assess reasoning quality, we present the Reasoning Evaluator, a novel automated system that objectively scores free-text reasoning responses based on efficiency, actuality, and completeness using dynamic cross-referencing and evidence checks. Using this benchmark, we evaluate five state-of-the-art reasoning LLMs, including DeepSeek-R1, OpenAI-o3-mini, and Gemini-2.0-Flash Thinking, etc. Our results show that current LLMs achieve over 85% accuracy in relatively simple diagnostic tasks when provided with sufficient examination results. However, performance declines in more complex tasks, such as examination recommendation and treatment planning. While reasoning outputs are generally reliable, with factuality scores exceeding 90%, critical reasoning steps are frequently missed. These findings underscore both the progress and limitations of clinical LLMs. Notably, open-source models like DeepSeek-R1 are narrowing the gap with proprietary systems, highlighting their potential to drive accessible and equitable advancements in healthcare.

Medical benchmark datasets significantly contribute to developing Large Language Models (LLMs) for medical knowledge extraction, diagnosis, summarization, and other uses. Yet, current benchmarks are mainly derived from exam questions given to medical students or cases described in the medical literature, lacking the complexity of real-world patient cases that deviate from classic textbook abstractions. These include rare diseases, uncommon presentations of common diseases, and unexpected treatment responses. Here, we construct Clinically Uncommon Patient Cases and Diagnosis Dataset (CUPCase) based on 3,562 real-world case reports from BMC, including diagnoses in open-ended textual format and as multiple-choice options with distractors. Using this dataset, we evaluate the ability of state-of-the-art LLMs, including both general-purpose and Clinical LLMs, to identify and correctly diagnose a patient case, and test models' performance when only partial information about cases is available. Our findings show that general-purpose GPT-4o attains the best performance in both the multiple-choice task (average accuracy of 87.9%) and the open-ended task (BERTScore F1 of 0.764), outperforming several LLMs with a focus on the medical domain such as Meditron-70B and MedLM-Large. Moreover, GPT-4o was able to maintain 87% and 88% of its performance with only the first 20% of tokens of the case presentation in multiple-choice and free text, respectively, highlighting the potential of LLMs to aid in early diagnosis in real-world cases. CUPCase expands our ability to evaluate LLMs for clinical decision support in an open and reproducible manner.

Clinical decision-making depends on expert reasoning, which is guided by standardized, evidence-based guidelines. However, translating these guidelines into automated clinical decision support systems risks inaccuracy and importantly, loss of nuance. We share an application architecture, the Large Language Expert (LLE), that combines the flexibility and power of Large Language Models (LLMs) with the interpretability, explainability, and reliability of Expert Systems. LLMs help address key challenges of Expert Systems, such as integrating and codifying knowledge, and data normalization. Conversely, an Expert System-like approach helps overcome challenges with LLMs, including hallucinations, atomic and inexpensive updates, and testability. To highlight the power of the Large Language Expert (LLE) system, we built an LLE to assist with the workup of patients newly diagnosed with cancer. Timely initiation of cancer treatment is critical for optimal patient outcomes. However, increasing complexity in diagnostic recommendations has made it difficult for primary care physicians to ensure their patients have completed the necessary workup before their first visit with an oncologist. As with many real-world clinical tasks, these workups require the analysis of unstructured health records and the application of nuanced clinical decision logic. In this study, we describe the design & evaluation of an LLE system built to rapidly identify and suggest the correct diagnostic workup. The system demonstrated a high degree of clinical-level accuracy (>95%) and effectively addressed gaps identified in real-world data from breast and colon cancer patients at a large academic center.

Background: Real-time treatment planning in IMRT is challenging due to complex beam interactions. AI has improved automation, but existing models require large, high-quality datasets and lack universal applicability. Deep reinforcement learning (DRL) offers a promising alternative by mimicking human trial-and-error planning. Purpose: Develop a stochastic policy-based DRL agent for automatic treatment planning with efficient training, broad applicability, and robustness against adversarial attacks using Fast Gradient Sign Method (FGSM). Methods: Using the Actor-Critic with Experience Replay (ACER) architecture, the agent tunes treatment planning parameters (TPPs) in inverse planning. Training is based on prostate cancer IMRT cases, using dose-volume histograms (DVHs) as input. The model is trained on a single patient case, validated on two independent cases, and tested on 300+ plans across three datasets. Plan quality is assessed using ProKnow scores, and robustness is tested against adversarial attacks. Results: Despite training on a single case, the model generalizes well. Before ACER-based planning, the mean plan score was 6.20$\pm$1.84; after, 93.09% of cases achieved a perfect score of 9, with a mean of 8.93$\pm$0.27. The agent effectively prioritizes optimal TPP tuning and remains robust against adversarial attacks. Conclusions: The ACER-based DRL agent enables efficient, high-quality treatment planning in prostate cancer IMRT, demonstrating strong generalizability and robustness.

Rare diseases are challenging to diagnose due to limited patient data and genetic diversity. Despite advances in variant prioritization, many cases remain undiagnosed. While large language models (LLMs) have performed well in medical exams, their effectiveness in diagnosing rare genetic diseases has not been assessed. To identify causal genes, we benchmarked various LLMs for gene prioritization. Using multi-agent and Human Phenotype Ontology (HPO) classification, we categorized patients based on phenotypes and solvability levels. As gene set size increased, LLM performance deteriorated, so we used a divide-and-conquer strategy to break the task into smaller subsets. At baseline, GPT-4 outperformed other LLMs, achieving near 30% accuracy in ranking causal genes correctly. The multi-agent and HPO approaches helped distinguish confidently solved cases from challenging ones, highlighting the importance of known gene-phenotype associations and phenotype specificity. We found that cases with specific phenotypes or clear associations were more accurately solved. However, we observed biases toward well-studied genes and input order sensitivity, which hindered gene prioritization. Our divide-and-conquer strategy improved accuracy by overcoming these biases. By utilizing HPO classification, novel multi-agent techniques, and our LLM strategy, we improved causal gene identification accuracy compared to our baseline evaluation. This approach streamlines rare disease diagnosis, facilitates reanalysis of unsolved cases, and accelerates gene discovery, supporting the development of targeted diagnostics and therapies.