Medical Image Synthesis

Unifying multimodal understanding and generation is a compelling frontier that is beginning to emerge in the medical field. However, the limited existing unified medical models typically treat understanding and generation as disjoint objectives, lacking a meaningful functional synergy. In this work, we identify and address a critical question in unified medical modeling: what form of understanding truly benefits generation. We present SynerMedGen, a unified framework built on the proposed principle of generation-aligned understanding, which synergizes understanding objectives with generation tasks via task alignment. SynerMedGen introduces three generation-aligned understanding tasks and a two-stage training strategy that transfers generation-beneficial representations learned during understanding training to medical image synthesis. Remarkably, even with understanding training alone, our SynerMedGen achieves strong zero-shot performance across 22 medical image synthesis tasks and demonstrates robust generalization to unseen datasets. When combined with generation training, SynerMedGen consistently outperforms state-of-the-art specialized medical image synthesis models as well as recent unified medical models. We also release a large-scale dataset named SynerMed consisting of 1M paired synthesis samples and 2M generation-derived understanding instances to support further research on understanding-generation synergy. Our project can be accessed at https://github.com/piooip/SynerMedGen.

Computed tomography (CT) is indispensable for clinical diagnosis and image-guided interventions but exposes patients to ionizing radiation, motivating the development of safer imaging alternatives. Ultrasound (US) is non-ionizing and widely accessible; however, it is highly operator dependent and lacks quantitative tissue characterization, often leading to diagnostic uncertainty and unnecessary CT examinations. This work presents a 3D ultrasound-derived pseudo-CT (UD-pCT) framework that generates CT-like anatomical reference volumes inferred from US, without aiming to reproduce physically accurate Hounsfield Units. Paired 3D kidney US and CT volumes from the TRUSTED dataset are first spatially aligned using a landmark-based multimodal registration pipeline, creating high-quality paired inputs for supervised training of an adversarial framework. The proposed Bottleneck Transformer Residual U-Net3D (BT-ResUNet3D) model employs a 3D residual encoder-decoder generator augmented with a transformer bottleneck, enabling effective modeling of fine-grained local anatomical structures as well as long-range volumetric dependencies, while a 3D Conditional PatchGAN discriminator enforces local structural realism in the synthesized pseudo-CT volumes. Quantitative evaluation using PSNR and SSIM demonstrates that the proposed method outperforms established baselines in structural fidelity and perceptual image quality. The UD-pCT volumes provide real-time anatomical reference for operator guidance, potentially reducing acquisition variability and unnecessary CT use. A limitation of this study is the relatively small paired dataset, which may limit the generalizability of the proposed model.

We propose a multimodal latent diffusion model that jointly synthesizes volumetric magnetic resonance imaging (MRI) and tabular clinical data within a shared latent space via cross-attention. This approach enables coherent joint representation learning of MRI and tabular modalities for generative modeling. Our model utilizes a variational autoencoder to fuse the two modalities before diffusion-based synthesis, allowing modality-appropriate reconstruction with separate decoders for MRI and tabular data. We evaluated the framework on data from the German National Cohort (NAKO Gesundheitsstudie), comprising over 10,000 participants with MRI scans and clinical tabular features such as age, sex, body measurements, and ethnicity. The generated MRI volumes exhibited anatomical plausibility and body composition consistent with the synthesized tabular attributes. Quantitative evaluation using Fréchet distance and precision-recall metrics confirmed high-fidelity image generation. In the tabular modality, our model outperformed CTGAN across standard evaluation metrics and achieved results comparable to TVAE, demonstrating competitive performance relative to established unimodal baselines. This work is, to our knowledge, the first to demonstrate the feasibility of jointly modeling MRI and mixed-type tabular data in a single latent diffusion framework, offering a proof-of-concept for generating coherent synthetic multimodal patient data and aligning with the broader goal of developing digital twins in healthcare.

Accurate histological differentiation between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) is critical for personalized treatment in non-small cell lung cancer (NSCLC). While [$^{18}$F]FDG PET/CT is a standard tool for the clinical evaluation of lung cancer, its utility is often limited by high costs and radiation exposure. In this paper, we investigate the feasibility of "virtual scanning" as a feature-enhancement strategy by evaluating whether synthetic PET data can provide complementary feature representations to supplement anatomical CT scans in histological subtype classification. We propose a framework that leverages a 3D Pix2Pix Generative Adversarial Network (GAN), pretrained on the FDG-PET/CT Lesions dataset, to synthesize pseudo-PET volumes from anatomical CT scans. These synthetic volumes are integrated with structural CT data within the MINT framework, a multi-stage intermediate fusion architecture. Our experiments, conducted on a multi-center dataset of 714 subjects, demonstrate that the inclusion of synthetic metabolic features significantly improves classification performance over a CT-only baseline. The multimodal approach achieved a statistically significant increase in the Area Under the Curve (AUC) from 0.489 to 0.591 and improved the Geometric Mean (GMean) from 0.305 to 0.524. These results suggest that synthetic PET scans provide discriminatory metabolic cues that enable deep learning models to exploit complementary cross-modal information, offering a potential feature-enhancement strategy for clinical scenarios where physical PET scans are unavailable.

Synthesizing longitudinal medical images at controllable disease stages while preserving patient-specific anatomy is hindered by the entanglement of pathological textures and structural features. We address this challenge for ulcerative colitis (UC) endoscopy, where severity follows a continuous ordinal progression along the Mayo Endoscopic Score (MES). Our framework, Disentangled Anatomy-Disease Diffusion (DADD), conditions a latent diffusion model on two complementary embeddings: a pretrained image encoder for patient anatomy and a separately trained ordinal embedder for cumulative disease severity. Since image embeddings inevitably capture disease information, we introduce a Feature Purifier, a cross-attention-based erasure mechanism that identifies and suppresses disease-correlated channels, yielding purified anatomical representations. These cleaned anatomy tokens and target disease tokens are injected into the denoising network via a Triple-Pathway Cross-Attention mechanism with resolution-dependent routing gates. This architecture leverages the U-Net hierarchy, in which different network depths encode global structure versus fine-grained pathological texture. Furthermore, we introduce Delta Steering, a training-free directional signal derived from the ordinal embeddings that enables explicit, single-pass control over disease transitions at inference without requiring additional forward passes. Validated on the LIMUC dataset, our approach produces high-fidelity images across all severity levels and effectively rebalances skewed class distributions, enhancing performance for downstream classification tasks. The dataset is available at zenodo.org/records/5827695 and the code base at github.com/umutdundar99/progressive-stable-diffusion

Generative Adversarial Networks (GANs) can help overcome data scarcity in computer vision tasks by generating additional training samples. In this work, we explore generative data augmentation in two low-resource domains: Bangla handwritten character recognition and chest X-ray image analysis. We use DCGAN-based models trained on 64x64 images to generate synthetic samples and evaluate their quality using Inception Score (IS), Fréchet Inception Distance (FID), and visualization methods such as t-SNE and UMAP. To measure practical usefulness, we train image classifiers using real data and a combination of real and synthetic data. Experimental results show that synthetic augmentation improves data diversity and consistently increases classification performance in limited-data settings. We also investigate training stability techniques, including gradient penalty and spectral normalization, and perform ablation studies on synthetic-to-real data ratios and sample filtering strategies. In addition, we discuss challenges related to medical image evaluation, dataset licensing, and privacy concerns of synthetic data. Our approach is simple, reproducible, and provides a strong baseline for generative augmentation in resource-constrained imaging applications.

Accelerated magnetic resonance imaging (MRI) enabled by the training of deep learning (DL)-based image recon. models requires large and diverse raw k-space datasets. In most clinical MRI applications, due to storage and patient privacy concerns, raw k-space data is discarded and magnitude-only images are the only component saved. Consequently, a large portion of the DL-based MRI recon. literature has either relied on small training datasets or has used one of the few available open-source k-space datasets. At the same time, the growing number of anonymized magnitude-only image registries/databases motivates the development of techniques that can use them as training datasets for generalizable DL-based recon. models. Here we propose to address this challenge by employing a generative approach based on conditional score-based diffusion models (SBDMs): given a magnitude-only MR image, it synthesizes a phase map (in the image domain) that realistically corresponds to the magnitude-only image. We evaluate its generative capabilities in a downstream DL-based recon. task whereby a large k-space dataset is generated by combining the SBDM-synthesized phase-maps and the corresponding magnitude-only images, and this k-space dataset is then used to train a DL model for accelerated MRI recon. We compare the performance of the resulting DL model versus those trained according to (a) a naive approach that uses smooth phase, (b) a k-space training dataset generated using synthesized phase maps derived from a generative adversarial network, and (c) the ground truth k-space data. Our results suggest that the DL model trained from SBDM-synthesized k-space data outperforms the other approaches in terms of quantitative metrics as well as qualitatively observed recon. fidelity, i.e., whether the reconstructed images include erroneous or hallucinated features that could adversely impact diagnostic accuracy.

Accurate synthesis of computed tomography (CT) images from magnetic resonance imaging (MRI) is clinically valuable for cranial applications such as attenuation correction, radiotherapy planning, and image-guided interventions. However, heterogeneity across MRI field strengths and acquisition protocols limits the generalizability of existing methods. In this study, we formulate cranial CT synthesis as a modular, structurally coupled problem and propose a deep learning framework to improve robustness across heterogeneous MRI conditions. The model is designed to adapt to variations in field strength and imaging protocols while preserving anatomical consistency. Experiments on multi-site datasets demonstrate improved performance and generalization compared with conventional approaches. The proposed method enables reliable CT synthesis across heterogeneous MRI settings, supporting broader clinical translation.

Diffusion models produce high-quality synthetic data but suffer from slow inference. We propose 3D Variable-Step Denoising Diffusion Probabilistic Model (VS-DDPM) a framework engineered to maintain generative quality while accelerating inference by several factors. We tested our approach on four tasks (missing MRI, tumor removal, MRI-to-sCT, and CBCT-to-sCT) within the BraTS2025 and SynthRAD2025 challenges. Designed for high efficiency under hardware and time constrains imposed by both challenges. VS-DDPM achieved state-of-the-art (SOTA) performance in missing MRI synthesis, yielding Dice scores of 0.80, 0.83, and 0.88 for the enhancing tumor, tumor core, and whole tumor regions, respectively, alongside a structural similarity index (SSIM) of 0.95. For MRI tumor removal, the model attained a root mean squared error (RMSE) of 0.053, a peak signal-to-noise ratio (PSNR) of 26.77, and an SSIM of 0.918. While the framework demonstrated competitive performance in MRI-to-sCT and CBCT-to-sCT tasks, it did not reach SOTA benchmarks, potentially due to sensitivities in data pre and post-processing pipelines or specific loss function configurations. These results demonstrate that VS-DDPM provides a robust and tunable solution for high-fidelity 3D medical image synthesis. The code is available in https://github.com/andre-fs-ferreira/SynthRAD_by_Faking_it.

Understanding and predicting the progression of neurodegenerative diseases remains a major challenge in medical AI, with significant implications for early diagnosis, disease monitoring, and treatment planning. However, most available longitudinal neuroimaging datasets are temporally sparse with a few follow-up scans per subject. This scarcity of temporal data limits our ability to model and accurately capture the continuous anatomical changes related to disease progression in individual subjects. To address this problem, we propose a novel 4D (3DxT) diffusion-based generative framework that effectively models and synthesizes longitudinal brain anatomy over time, conditioned on available clinical variables such as health status, age, sex, and other relevant factors. Moreover, while most current approaches focus on manipulating image intensity or texture, our method explicitly learns the data distribution of topology-preserving spatiotemporal deformations to effectively capture the geometric changes of brain structures over time. This design enables the realistic generation of future anatomical states and the reconstruction of anatomically consistent disease trajectories, providing a more faithful representation of longitudinal brain changes. We validate our model through both synthetic sequence generation and downstream longitudinal disease classification, as well as brain segmentation. Experiments on two large-scale longitudinal neuroimage datasets demonstrate that our method outperforms state-of-the-art baselines in generating anatomically accurate, temporally consistent, and clinically meaningful brain trajectories. Our code is available on Github.

Gadoxetate disodium-enhanced MRI is essential for the detection and characterization of hepatocellular carcinoma. However, acquisition of the hepatobiliary phase (HBP) requires a prolonged post-contrast delay, which reduces workflow efficiency and increases the risk of motion artifacts. In this study, we propose a Triple-Phase Sequential Fusion Network (TriPF-Net) to synthesize HBP images by leveraging the sequential information from pre-HBP sequences: while T1-weighted imaging serves as the indispensable baseline, the model adaptively integrates arterial-phase (AP) and venous-phase (VP) features when available. By modeling the tissue-specific contrast uptake and excretion dynamics across these three phases, TriPF-Net ensures robust HBP synthesis even under the stochastic absence of one or both dynamic contrast-enhanced sequences. The framework comprises an Enhanced Region-Guided Encoder and a Dynamic Feature Unification Module, optimized with a Region-Guided Sequential Fusion Loss to maintain physiological consistency. In addition, clinical variables, including age, sex, total bilirubin, and albumin, are incorporated to enhance physiological consistency. Compared with conventional methods, TriPF-Net achieved superior performance on datasets from two centers. On the internal dataset, the model achieved an MAE of 10.65, a PSNR of 23.27, and an SSIM of 0.76. On the external validation dataset, the corresponding values were 12.41, 23.11, and 0.78, respectively. This flexible solution enhances clinical workflow and lesion depiction, potentially eliminating the need for delayed HBP acquisition in HCC imaging.

Diffusion models have achieved remarkable quality in multi-modal MRI synthesis, but their computational cost (hundreds of sampling steps and separate models per modality) limits clinical deployment. We observe that this inefficiency stems from an unnecessary starting point: diffusion begins from pure noise, discarding the structural information already present in available MRI sequences. We propose WFM (Wavelet Flow Matching), which instead learns a direct flow from an informed prior, the mean of conditioning modalities in wavelet space, to the target distribution. Because the source and target share underlying anatomy and differ primarily in contrast, this formulation enables accurate synthesis in just 1-2 integration steps. A single 82M-parameter model with class conditioning synthesizes all four BraTS modalities (T1, T1c, T2, FLAIR), replacing four separate diffusion models totaling 326M parameters. On BraTS 2024, WFM achieves 26.8 dB PSNR and 0.94 SSIM, within 1-2 dB of diffusion baselines, while running 250-1000x faster (0.16-0.64s vs. 160s per volume). This speed-quality trade-off makes real-time MRI synthesis practical for clinical workflows. Code is available at https://github.com/yalcintur/WFM.

Conditional medical image generation plays an important role in many clinically relevant imaging tasks. However, existing methods still face a fundamental challenge in balancing inference efficiency, patient-specific fidelity, and distribution-level plausibility, particularly in high-dimensional 3D medical imaging. In this work, we propose GDM, a generative drifting framework that reformulates deterministic medical image prediction as a multi-objective learning problem to jointly promote distribution-level plausibility and patient-specific fidelity while retaining one-step inference. GDM extends drifting to 3D medical imaging through an attractive-repulsive drift that minimizes the discrepancy between the generator pushforward and the target distribution. To enable stable drifting-based learning in 3D volumetric data, GDM constructs a multi-level feature bank from a medical foundation encoder to support reliable affinity estimation and drifting field computation across complementary global, local, and spatial representations. In addition, a gradient coordination strategy in the shared output space improves optimization balance under competing distribution-level and fidelity-oriented objectives. We evaluate the proposed framework on two representative tasks, MRI-to-CT synthesis and sparse-view CT reconstruction. Experimental results show that GDM consistently outperforms a wide range of baselines, including GAN-based, flow-matching-based, and SDE-based generative models, as well as supervised regression methods, while improving the balance among anatomical fidelity, quantitative reliability, perceptual realism, and inference efficiency. These findings suggest that GDM provides a practical and effective framework for conditional 3D medical image generation.

Digital subtraction angiography (DSA) in coronary imaging is fundamentally challenged by physiological motion, forcing reliance on raw angiograms cluttered with anatomical noise. Existing deep learning methods often produced images with two critical clinically unacceptable flaws: persistent boundary artifacts and a loss of native tissue grayscale fidelity that undermined diagnostic confidence. We propose a novel framework termed as CDSA-Net that for the first time explicitly decouples and jointly optimizes vascular structure preservation and realistic background restoration. CDSA-Net introduces two core innovations: (i) A hierarchical geometric prior guidance (HGPG) mechanism, embedded in our coronary structure extraction network (CSENet). It synergistically combines integrated geometric prior (IGP) with gated spatial modulation (GSM) and centerline-aware topology (CAT) loss supervision, ensuring structural continuity. (ii) An adaptive noise module (ANM) within our coronary background restoration network (CBResNet). Unlike standard restoration, ANM uniquely models the stochastic nature of clinical X-ray noise, bridging the domain gap to enable seamless background intensity estimation and the complete elimination of boundary artifacts. The final subtraction is obtained by removing the restored background from the raw angiogram. Quantitatively, it significantly outperformed state-of-the-art methods in vascular intensity correlation and perceptual quality. A 25.6% improvement in morphology assessment efficiency and a 42.9% gain in hemodynamic evaluation speed set a new benchmark for utility in interventional cardiology, while maintaining diagnostic results consistent with raw angiograms. The project code is available at https://github.com/DrThink-ai/CDSA-Net.

Latent diffusion models have emerged as powerful generative models in medical imaging, enabling the synthesis of high quality brain magnetic resonance imaging scans. In particular, predicting the evolution of a patients brain can aid in early intervention, prognosis, and treatment planning. In this study, we introduce CLIMB, Controllable Longitudinal brain Image generation via state space based latent diffusion model, an advanced framework for modeling temporal changes in brain structure. CLIMB is designed to model the structural evolution of the brain structure over time, utilizing a baseline MRI scan and its acquisition age as foundational inputs. Additionally, multiple conditional variables, including projected age, gender, disease status, genetic information, and brain structure volumes, are incorporated to enhance the temporal modeling of anatomical changes. Unlike existing LDM methods that rely on self attention modules, which effectively capture contextual information from input images but are computationally expensive, our approach leverages state space, a state space model architecture that substantially reduces computational overhead while preserving high-quality image synthesis. Furthermore, we introduce a Gaussian-aligned autoencoder that extracts latent representations conforming to prior distributions without the sampling noise inherent in conventional variational autoencoders. We train and evaluate our proposed model on the Alzheimers Disease Neuroimaging Initiative dataset, consisting of 6,306 MRI scans from 1,390 participants. By comparing generated images with real MRI scans, CLIMB achieves a structural similarity index of 0.9433, demonstrating notable improvements over existing methods.

Objective. Standard Magnetic Resonance Imaging (MRI) reconstruction pipelines discard phase information captured during acquisition, despite evidence that it encodes tissue properties relevant to tumor diagnosis. Current machine learning approaches inherit this limitation by operating exclusively on reconstructed magnitude images. The aim of this study is to build a generative framework which is capable of jointly modeling magnitude and phase information of complex-valued MRI scans. Approach. The proposed generative framework combines a conditional variational autoencoder, which compresses complex-valued MRI scans into compact latent representations while preserving phase coherence, with a flow-matching-based generative model. Synthetic sample quality is assessed via a real-versus-synthetic classifier and by training downstream classifiers on synthetic data for abnormal tissue detection. Main results. The autoencoder preserves phase coherence above 0.997. Real-versus-synthetic classification yields low AUROC values between 0.50 and 0.66 across all acquisition sequences, indicating generated samples are nearly indistinguishable from real data. In downstream normal-versus-abnormal classification, classifiers trained entirely on synthetic data achieve an AUROC of 0.880, surpassing the real-data baseline of 0.842 on a publicly available dataset (fastMRI). This advantage persists on an independent external test set from a different institution with biopsy-confirmed labels. Significance. The proposed framework demonstrates the feasibility of jointly modeling magnitude and phase information for normal and abnormal complex-valued brain MRI data. Beyond synthetic data generation, it establishes a foundation for the usage of complete brain MRI information in future diagnostic applications and enables systematic investigation of how magnitude and phase jointly encode pathology-specific features.

Computed tomography (CT) provides rich 3D anatomical detail but is often constrained by high radiation exposure, substantial costs, and limited availability. Standard chest X-rays are cost-effective and widely accessible, but provide only 2D projections with limited pathological information. Reconstructing 3D CT volumes from 2D X-rays could markedly increase diagnostic accessibility, yet existing methods rely predominantly on synthetic X-ray projections, limiting clinical generalization. We propose AXON, a multi-stage diffusion-based framework that reconstructs 3D CT volumes directly from real X-rays with substantially improved fidelity over existing approaches. AXON follows a coarse-to-fine paradigm: a Brownian Bridge diffusion model first captures global anatomical structure, and a ControlNet-guided refinement stage then enhances local intensity detail and anatomical realism. To alleviate the depth ambiguity inherent in 2D-to-3D reconstruction, AXON incorporates bi-planar X-ray views, enabling more accurate spatial reasoning and structural recovery. A dedicated super-resolution module further increases the spatial resolution of the generated volumes. Experiments on public and external datasets show that AXON consistently surpasses state-of-the-art approaches while generalizing across diverse clinical distributions. At our highest-resolution bi-planar setting, AXON achieves an 11.9% improvement in PSNR and an 11.0% increase in SSIM over the strongest baseline evaluated at that resolution. In the $128^3$ single-planar setting, it maintains a lead of 7.8% in PSNR on LIDC-IDRI, with larger margins on the external clinical dataset of 8.0% in PSNR and 16.9% in SSIM. Our code is available at https://github.com/ai-med/AXON/.

Radiotherapy workflows for oncological patients increasingly rely on multi-modal medical imaging, commonly involving both Magnetic Resonance Imaging (MRI) and Computed Tomography (CT). MRI-only treatment planning has emerged as an attractive alternative, as it reduces patient exposure to ionizing radiation and avoids errors introduced by inter-modality registration. While nnU-Net-based frameworks are predominantly used for MRI-to-CT synthesis, we explore Mamba-based architectures for this task to investigate the applicability of state-space modeling for cross-modality medical image translation and assess its performance relative to established convolutional architectures. Specifically, we adapt the SegMamba architecture, originally proposed for segmentation, to perform image-to-image generation. Our 3D Mamba architecture effectively captures complex volumetric features and long-range dependencies, thus allowing accurate CT synthesis while maintaining a relatively low parameter count. Experiments were conducted on a subset of SynthRAD2025 dataset, comprising registered single-channel MRI-CT volume pairs across three anatomical regions. Quantitative evaluation is performed via a combination of image similarity metrics computed in Hounsfield Units (HU) and segmentation-based metrics obtained from TotalSegmentator to ensure geometric consistency is preserved. The findings pave the way for the integration of state-space models into radiotherapy workflows.

Medical image generators trained on imbalanced data can fail at demographic intersections absent from training. We introduce CompDiff, which encodes age, sex and race separately and composes supervised demographic tokens alongside clinical text. Across chest radiographs and fundus images, CompDiff improves overall and subgroup fidelity relative to prompt conditioning (RoentGen-v2) and loss reweighting (FairDiffusion). It generalises in zero-shot generation to 16 chest X-ray intersections excluded from training, achieving the lowest mean FID-RadImageNet in every intersection. In a blinded reader study of these unseen intersections, two radiologists gave CompDiff the highest mean scores among generators for anatomical realism and agreement with the clinical impression, and selected its images most often as the most realistic. Pretraining with CompDiff images improved downstream classification, while CompDiff audit cohorts reduced estimation error on rare intersections. These findings support compositional demographic conditioning for extending medical image synthesis to underserved populations. Code: https://github.com/mahmoudibrahim98/CompDiff

Lung cancer remains the leading cause of cancer-related mortality worldwide, with survival outcomes critically dependent on early and accurate detection. When low-dose computed tomography (LDCT) findings are indeterminate, clinicians typically defer diagnosis pending follow-up CT imaging obtained up to 12 months later, inevitably delaying treatment for patients with malignant nodules. To address this clinical gap, we propose Nodule-Aligned Multimodal (Latent) Diffusion (NAMD), a novel generative framework that synthesizes one-year follow-up nodule CT images conditioned on the baseline CT scan, quantitative nodule biomarkers, and patient-level Electronic Health Records (EHR), enabling timely prediction of nodule malignant progression without requiring actual follow-up scans. NAMD introduces two key contributions: (i) a nodule-aligned latent space regularized so that embedding distances reflect clinically meaningful biomarker changes, and (ii) an LLM-driven multimodal conditioning mechanism encoding heterogeneous EHR data into the diffusion backbone. Evaluated on the National Lung Screening Trial (NLST), our method's synthetic follow-up images achieve an AUROC of 0.805 and an AUPRC of 0.346 for lung nodule malignancy prediction, outperforming both the baseline LDCT performance without virtual follow-up generation, and existing state-of-the-art conditional generation methods, while maintaining competitive image quality. These findings suggest that NAMD enables earlier and more accurate lung cancer diagnosis by capturing clinically meaningful features of nodule progression.

Medical image analysis depends on accurate segmentation and controllable synthesis, but both tasks face severe spatial imbalance: lesions occupy small regions against large backgrounds. We study adaptive spatial weighting as a task-level design principle and instantiate it in two adapters. LAW learns per-pixel loss weights for mask-conditioned diffusion by modulating a ratio prior with a feature-dependent delta map, with normalization, clamping, and Dice regularization for stability. ORDER improves lightweight segmentation by adding selective bidirectional skip attention with stage-wise confidence gating. On held-out diffusion test sets, LAW lowers FID from 158.13$\pm$0.15 to 108.43$\pm$0.71 on Polyps, from 144.13$\pm$0.31 to 89.51$\pm$0.96 on KiTS19, and from 139.22$\pm$0.38 to 112.58$\pm$0.68 on BRISC, while improving held-out mask-recovery Dice from 0.681$\pm$0.013 to 0.825$\pm$0.003 on Polyps. When the resulting images are added to nnUNet training, downstream Polyps mDice rises from 71.7$\pm$0.4 to 74.1$\pm$0.8. On the cleaned Polyps segmentation protocol, the reported ORDER configuration reaches 76.3$\pm$1.9 mDice and 67.2$\pm$2.0 mIoU at 42K parameters and 0.11 GFLOPs, versus 70.3$\pm$1.5 mDice and 59.9$\pm$1.7 mIoU for matched MK-UNet. On BRISC under the same training recipe, ORDER reaches 77.4$\pm$0.8 mDice and 68.1$\pm$0.7 mIoU. These results position adaptive spatial weighting as a practical design idea for both medical diffusion and efficient segmentation.

Tau positron emission tomography supports Alzheimer's disease staging but is difficult to scale because of tracer, scanner, and radiation constraints. Synthesis from structural MRI is therefore attractive, but it is a particularly difficult setting. T1-weighted and FLAIR MRI provide anatomy and disease correlated morphology, but they do not directly measure Tau-PET relevant signal. We introduce SFL-Net, a multi-input synthesis framework that predicts Tau-PET from T1-weighted and FLAIR MRI. SFL-Net factorizes the latent representation into shared, T1-specific, FLAIR-specific, and complementary pathways and preserves anatomical detail through latent structural conditioning rather than direct encoder-decoder connections. We evaluated SFL-Net and baseline models using 605 training and 83 validation subjects from ADNI-3 and OASIS-3 datasets. Evaluation included raw image fidelity, standardized uptake value ratio agreement, high uptake overlap, regional Bland-Altman bias, braak derived stage agreement, non-inferiority sensitivity analysis, and latent component Shapley attribution. SFL-Net performed competitively on both clinically relevant and reconstruction metrics, while also delivering explicit source level auditability that conventional UNet derived models lack.

Self-supervised learning (SSL) and diffusion models have respectively advanced representation learning and generative modeling for high-dimensional 3D visual data, yet they are often developed as separate paradigms. Their unification remains challenging under multi-source heterogeneity, as anatomical content must be preserved for analysis while acquisition-related style varies across centers and affects synthesis. In this paper, we propose MeDUET, a 3D Medical image Disentangled UnifiEd PreTraining framework in the variational autoencoder latent space. MeDUET formulates unified pretraining as an empirical factor identifiability problem, aiming to learn domain-invariant content factors for anatomy and domain-specific style factors for appearance. To improve factor separation, MeDUET first uses token demixing with a standard adversarial domain regularizer to establish basic content-style specialization, and further introduces Mixed Factor Token Distillation and Swap-invariance Quadruplet Contrast to reduce mixed-region factor leakage and organize factor spaces with factor-wise invariance and discriminability. With these learned factors, MeDUET transfers effectively to both synthesis and analysis, yielding higher fidelity, faster convergence, and better controllability for synthesis, while achieving competitive or superior domain generalization and label efficiency on diverse datasets, tasks, and modalities. Overall, MeDUET shows that multi-source heterogeneity can serve as useful supervision, with disentanglement providing an effective interface for unifying 3D medical image synthesis and analysis. Our code is available at https://github.com/JK-Liu7/MeDUET.

Autoregressive pretraining has been key to the scalability of large language models, yet medical generative foundation models remain predominantly based on diffusion. Here we introduce MedVAR, the first foundation model for all-round medical image generation through autoregressive training, and find it offers improved generation quality and efficiency, stronger scalability, and broader adaptability to downstream clinical tasks than diffusion-based models. A tokenizer trained on medical images and separate semantic and structural controls enable generation across six anatomical regions in computed tomography and magnetic resonance imaging. Trained on 438,905 slices from 40 datasets, including seven internal clinical centres, MedVAR generates images 12-19 times faster than 100-step diffusion baselines. Generation quality improves with model size. Pretraining on generated images improves seven-centre hepatocellular carcinoma segmentation Dice from 0.615 to 0.632, while reconstruction using MedVAR images approaches the volumetric segmentation performance of fully sampled volumes. Membership inference reaches 3.54% sensitivity at a 1% false-positive rate, while copy detection performs near chance. These findings establish next-scale autoregression as a scalable and versatile approach to medical image generation and downstream analysis.

Cardiac Magnetic Resonance (CMR) imaging provides a comprehensive assessment of cardiac structure and function but remains constrained by high acquisition costs and reliance on expert annotations, limiting the availability of large-scale labeled datasets. In contrast, electrocardiograms (ECGs) are inexpensive, widely accessible, and offer a promising modality for conditioning the generative synthesis of cine CMR. To this end, we propose ECGFlowCMR, a novel ECG-to-CMR generative framework that integrates a Phase-Aware Masked Autoencoder (PA-MAE) and an Anatomy-Motion Disentangled Flow (AMDF) to address two fundamental challenges: (1) the cross-modal temporal mismatch between multi-beat ECG recordings and single-cycle CMR sequences, and (2) the anatomical observability gap due to the limited structural information inherent in ECGs. Extensive experiments on the UK Biobank and a proprietary clinical dataset demonstrate that ECGFlowCMR can generate realistic cine CMR sequences from ECG inputs, enabling scalable pretraining and improving performance on downstream cardiac disease classification and phenotype prediction tasks.

Accurately modeling longitudinal brain MRI progression is crucial for understanding neurodegenerative diseases and predicting individualized structural changes. Existing state-of-the-art approaches, such as Brain Latent Progression (BrLP), often use multi-stage training pipelines with auxiliary conditioning modules but suffer from architectural complexity, suboptimal use of conditional clinical covariates, and limited guarantees of anatomical consistency. We propose Anatomically Guided Latent Diffusion Model (AG-LDM), a segmentation-guided framework that enforces anatomically consistent progression while substantially simplifying the training pipeline. AG-LDM conditions latent diffusion by directly fusing baseline anatomy, noisy follow-up states, and clinical covariates at the input level, a strategy that avoids auxiliary control networks by learning a unified, end-to-end model that represents both anatomy and progression. A lightweight 3D tissue segmentation model (WarpSeg) provides explicit anatomical supervision during both autoencoder fine-tuning and diffusion model training, ensuring consistent brain tissue boundaries and morphometric fidelity. Experiments on 31,713 ADNI longitudinal pairs and zero-shot evaluation on OASIS-3 demonstrate that AG-LDM matches or surpasses more complex diffusion models, achieving highly competitive image quality and 15-20% reduction in volumetric errors in generated images. AG-LDM also exhibits markedly stronger utilization of temporal and clinical covariates (3.5-31.5x higher covariate sensitivity than BrLP) and generates biologically plausible counterfactual trajectories, accurately capturing hallmarks of Alzheimer's progression such as limbic atrophy and ventricular expansion. These results highlight AG-LDM as an efficient, anatomically grounded framework for reliable brain MRI progression modeling.

Expert-annotated training data remains the critical bottleneck for AI in histopathology, particularly for rare pathologies where even dozens of cases may be unavailable. While data augmentation offers a solution, existing methods fail to generate sufficiently realistic lesion morphologies that preserve tissue-specific architectures. Here we present PathoGen, a diffusion-based generative model enabling controllable, high-fidelity lesion inpainting into benign histopathology images. We validate PathoGen across four datasets representing kidney, skin, breast, and prostate pathology. Quantitative assessment confirms PathoGen outperforms state-of-the-art baselines in image fidelity and distributional similarity. Evaluation by six expert pathologists revealed that synthetic images by PathoGen were only marginally distinguished from real tissue image slightly above chance (57.75% accuracy), demonstrating strong perceptual realism of PathoGen-generated lesions. PathoGen achieved the highest win rate (35.4%) when pathologists ranked generation quality against all baselines. Crucially, augmenting training sets with PathoGen-synthesized lesions improves segmentation Dice scores by up to 0.18 compared to traditional augmentations, with maximum benefit in data-scarce regimes. By simultaneously generating realistic morphology and pixel-level annotations, PathoGen effectively addresses both data scarcity and annotation cost, two critical bottlenecks in computational pathology development.

Synthetic medical image data can unlock the potential of deep learning (DL)-based clinical decision support (CDS) systems through the creation of large scale, privacy-preserving, training sets. Despite the significant progress in this field, there is still a largely unanswered research question: "How can we quantitatively assess the similarity of a synthetically generated set of images with a set of real images in a given application domain?". Today, answers to this question are mainly provided via user evaluation studies, inception-based measures, and the classification performance achieved on synthetic images. This paper proposes a novel measure to assess the similarity between synthetically generated and real sets of images, in terms of their utility for the development of DL-based CDS systems. Inspired by generalized neural additive models, and unlike inception-based measures, the proposed measure is interpretable (Interpretable Utility Similarity, IUS), explaining why a synthetic dataset could be more useful than another one in the context of a CDS system based on clinically relevant image features. The experimental results on publicly available benchmark datasets from various color medical imaging modalities including endoscopic, dermoscopic and fundus imaging, indicate that selecting synthetic images of high utility similarity using IUS can result in relative improvements of up to 54.6% in terms of classification performance. The generality of IUS for synthetic data assessment is demonstrated also for grayscale X-ray and ultrasound imaging modalities. IUS implementation is available at https://github.com/innoisys/ius.

Brain tumors induce complex structural deformations that obscure the patient' s original neuroanatomy, making it difficult to distinguish tumor-induced changes from inherent anatomical variability. Reconstructing a subject-specific pseudo-healthy brain can provide a critical reference for such analysis, but this task is inherently counterfactual, as paired pre-tumor scans and explicit healthy guidance are unavailable. We propose BrainNormalizer, a diffusion-based framework for subject-specific pseudo-healthy brain MRI reconstruction that enables anatomy-informed reconstruction without requiring paired data or explicit healthy references. The framework learns anatomical priors and edge-based structural conditioning through a two-stage training strategy consisting of inpainting-based diffusion fine-tuning and ControlNet-based edge conditioning. At inference, counterfactual pseudo-healthy reconstruction is achieved through a deliberate misalignment strategy, where tumorous inputs are paired with non-tumorous prompts and mirrored contralateral edge maps. This allows subject-specific anatomical guidance to be constructed from the patient's own anatomy, enabling anatomically consistent pseudo-healthy reconstruction that preserves individual structural characteristics. Experiments on the BraTS2020 dataset demonstrate that BrainNormalizer achieves improved distributional realism, symmetry-based structural consistency, and reduced false positive detection compared to existing methods. These results indicate that the proposed framework provides a principled approach for subject-specific counterfactual reconstruction and supports downstream analysis of tumor-induced deformation.

Generative modeling frameworks have emerged as an effective approach to capture high-dimensional image distributions from large datasets without requiring domain-specific knowledge, a capability essential for disease progression modeling. Recent generative approaches have attempted to capture progression by mapping images to a latent space and guiding representations to generate follow-up images from previous time points. However, these methods impose constraints on distribution learning, resulting in latent spaces with limited controllability for generating follow-up images without paired subject-specific longitudinal guidance. In order to enable controlled movements in the latent representational space and generate progression images from a previous time-point image without subject-specific guidance, we introduce a conditionable Diffusion Auto-encoder framework that forms a compact latent space capturing high-level semantics and providing means to control generation. Our approach leverages this latent space to condition and apply controlled shifts to the representations of previous time-point images by isolating progression and subject identity information for generating follow-up images. The shifts are implicitly guided by correlating with progression attributes and constraining to Alzheimer's disease specific regions, without paired longitudinal guidance. We validate the generations through image quality metrics, volumetric progression analysis, and downstream tasks in Alzheimer's disease datasets from different sources. This demonstrates the effectiveness of our approach for Alzheimer's progression modeling and longitudinal image generation.