Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most formidable challenges in oncology, characterized by its late detection and poor prognosis. Artificial intelligence (AI) and machine learning (ML) are emerging as pivotal tools in revolutionizing PDAC care across various dimensions. Consequently, many studies have focused on using AI to improve the standard of PDAC care. This review article attempts to consolidate the literature from the past five years to identify high-impact, novel, and meaningful studies focusing on their transformative potential in PDAC management. Our analysis spans a broad spectrum of applications, including but not limited to patient risk stratification, early detection, and prediction of treatment outcomes, thereby highlighting AI’s potential role in enhancing the quality and precision of PDAC care. By categorizing the literature into discrete sections reflective of a patient’s journey from screening and diagnosis through treatment and survivorship, this review offers a comprehensive examination of AI-driven methodologies in addressing the multifaceted challenges of PDAC. Each study is summarized by explaining the dataset, ML model, evaluation metrics, and impact the study has on improving PDAC-related outcomes. We also discuss prevailing obstacles and limitations inherent in the application of AI within the PDAC context, offering insightful perspectives on potential future directions and innovations.

For many patients, the cancer continuum includes a syndrome known as cancer-associated cachexia (CAC), which encompasses the unintended loss of body weight and muscle mass, and is often associated with fat loss, decreased appetite, lower tolerance and poorer response to treatment, poor quality of life, and reduced survival. Unfortunately, there are no effective therapeutic interventions to completely reverse cancer cachexia and no FDA-approved pharmacologic agents; hence, new approaches are urgently needed. In May of 2022, researchers and clinicians from Moffitt Cancer Center held an inaugural retreat on CAC that aimed to review the state of the science, identify knowledge gaps and research priorities, and foster transdisciplinary collaborative research projects. This review summarizes research priorities that emerged from the retreat, examples of ongoing collaborations, and opportunities to move science forward. The highest priorities identified include the need to (1) evaluate patient-reported outcome (PRO) measures obtained in clinical practice and assess their use in improving CAC-related outcomes; (2) identify biomarkers (imaging, molecular, and/or behavioral) and novel analytic approaches to accurately predict the early onset of CAC and its progression; and (3) develop and test interventions (pharmacologic, nutritional, exercise-based, and through mathematical modeling) to prevent CAC progression and improve associated symptoms and outcomes.

Intraductal papillary mucinous neoplasms (IPMN) are commonly detected pancreatic cysts that may transform into pancreatic ductal adenocarcinoma (PDAC). Predicting which IPMNs will progress to PDAC remains a clinical challenge. Moreover, identifying those clinically evident IPMNs for which a surveillance approach is best is a dire clinical need. Therefore, we aimed to identify molecular signatures that distinguished between PDAC with and without clinical evidence of an IPMN to identify novel molecular pathways related to IPMN-derived PDAC that could help guide biomarker development. Data from the Oncology Research Information Exchange Network (ORIEN) multi-institute sequencing project were utilized to analyze 66 PDAC cases from Moffitt Cancer Center and The Ohio State University Wexner Medical Center, for which tumor whole transcriptome sequencing datasets were generated. Cases were classified based on whether a tumor had originated from an IPMN (n = 16) or presumably through the pancreatic intraepithelial neoplasia (PanIN) pathway (n = 50). We then performed differential expression and pathway analysis using Gene-Set Enrichment Analysis (GSEA) and Pathway Analysis with Down-weighted Genes (PADOG) algorithms. We also analyzed immune profiles using the Tumor-Immune Microenvironment Deconvolution web portal for Bulk Transcriptomics (TIMEx). Both GSEA and TIMEx indicate that PanIN-derived PDAC tumors enrich inflammatory pathways (complement, hedgehog signaling, coagulation, inflammatory response, apical surface, IL-2/STAT5, IL-6/STAT3, EMT, KRAS signaling, apical junction, IFN-gamma, allograft rejection) and are comparatively richer in almost all immune cell types than those from IPMN-derived PDAC. IPMN-derived tumors were enriched for metabolic and energy-generating pathways (oxidative phosphorylation, unfolded protein response, pancreas beta cells, adipogenesis, fatty acid metabolism, protein secretion), and the most significantly upregulated genes (padj < 0.001) included mucin 2 (MUC2) and gastrokine-2 (GKN2). Further, the metabolic-linked gene signature enriched in the IPMN-derived samples is associated with a cluster of early-stage and long-survival (top 4th quartile) PDAC cases from The Cancer Genome Atlas (TCGA) expression database. Our data suggest that IPMN-derived and PanIN-derived PDACs differ in the expression of immune profiles and metabolic pathways. These initial findings warrant validation and follow-up to develop biomarker-based strategies for early PDAC detection and treatment.

Loss of skeletal muscle mass in cancer cachexia is associated with poorer survival, reduced treatment tolerance, and diminished quality of life. Routine oncology computed tomography (CT) can yield skeletal muscle area (SMA) and skeletal muscle index (SMI) for early cachexia assessment and prognostication, but manual annotation is labor intensive and existing automated tools often show inconsistent reliability. We developed SMAART-AI (Skeletal Muscle Assessment—Automated and Reliable Tool based on AI), a fully automated pipeline that localizes the third lumbar (L3) vertebral level, segments skeletal muscle, and quantifies prediction uncertainty to flag potentially unreliable outputs. Performance and reliability were evaluated across gastroesophageal, pancreatic, colorectal, and ovarian cancer cohorts, benchmarking against expert annotations and existing tools. SMAART-AI achieved a Dice score of 97.80% ± 0.93% in gastroesophageal cancer and a median SMA deviation of 2.48% from expert annotations across pancreatic, colorectal, and ovarian cohorts. Uncertainty scores correlated strongly with prediction error, enabling identification of high-error cases to support trustworthy deployment. Integrating the SMA/SMI with clinical features and body mass index (BMI) improved survival prediction (concordance index was +2.19% for colorectal, +9.82% for pancreatic, and +2.58% for ovarian cancer) and supported cachexia detection (70.00% accuracy; F1 80.00%). Overall, SMAART-AI provides an uncertainty-aware, clinically translatable framework for scalable CT-based muscle assessment and improved oncologic prognostication.

Cancer cachexia, a multifactorial metabolic syndrome characterized by severe muscle wasting and weight loss, contributes to poor outcomes across various cancer types but lacks a standardized, generalizable biomarker for early detection. We present a multimodal AI-based biomarker trained on real-world clinical, radiologic, laboratory, and unstructured clinical note data, leveraging foundation models and large language models (LLMs) to identify cachexia at the time of cancer diagnosis. Prediction accuracy improved with each added modality: 77% using clinical variables alone, 81% with added laboratory data, and 85% with structured symptom features extracted from clinical notes. Incorporating embeddings from clinical text and CT images further improved accuracy to 92%. The framework also demonstrated prognostic utility, improving survival prediction as data modalities were integrated. Designed for real-world clinical deployment, the framework accommodates missing modalities without requiring imputation or case exclusion, supporting scalability across diverse oncology settings. Unlike prior models trained on curated datasets, our approach utilizes standard-of-care clinical data, facilitating integration into oncology workflows. In contrast to fixed-threshold composite indices such as the cachexia index (CXI), the model generates patient-specific predictions, enabling adaptable, cancer-agnostic performance. To enhance clinical reliability and safety, the framework incorporates uncertainty estimation to flag low-confidence cases for expert review. This work advances a clinically applicable, scalable, and trustworthy AI-driven decision support tool for early cachexia detection and personalized oncology care.

Cancer cachexia is a common metabolic disorder characterized by severe muscle atrophy which is associated with poor prognosis and quality of life. Monitoring skeletal muscle area (SMA) longitudinally through computed tomography (CT) scans, an imaging modality routinely acquired in cancer care, is an effective way to identify and track this condition. However, existing tools often lack full automation and exhibit inconsistent accuracy, limiting their potential for integration into clinical workflows. To address these challenges, we developed SMAART-AI (Skeletal Muscle Assessment-Automated and Reliable Tool-based on AI), an end-to-end automated pipeline powered by deep learning models (nnU-Net 2D) trained on mid-third lumbar level CT images with 5-fold cross-validation, ensuring generalizability and robustness. SMAART-AI incorporates an uncertainty-based mechanism to flag high-error SMA predictions for expert review, enhancing reliability. We combined the SMA, skeletal muscle index, BMI, and clinical data to train a multi-layer perceptron (MLP) model designed to predict cachexia at the time of cancer diagnosis. Tested on the gastroesophageal cancer dataset, SMAART-AI achieved a Dice score of 97.80% ± 0.93%, with SMA estimated across all four datasets in this study at a median absolute error of 2.48% compared to manual annotations with SliceOmatic. Uncertainty metrics — variance, entropy, and coefficient of variation — strongly correlated with SMA prediction errors (0.83, 0.76, and 0.73 respectively). The MLP model predicts cachexia with 79% precision, providing clinicians with a reliable tool for early diagnosis and intervention. By combining automation, accuracy, and uncertainty awareness, SMAART-AI bridges the gap between research and clinical application, offering a transformative approach to managing cancer cachexia.