PET Quantification-Preserving Registration for Longitudinal Whole-Body PSMA PET/CT

Raw image intensities are a poor surrogate for similarity across images in correspondence problems. Further, while auxiliary segmentation labels can provide semantic identification and improve matching, they can assign only coarse identities to fine-grained anatomy and often cover only a subset of structures, particularly in whole-body settings. We present an approach that instead establishes correspondence using complementary representations of anatomy and demonstrate its utility for longitudinal whole-body PET/CT registration in the Learn2Reg 2026 PSMAReg Challenge. We use our 3D foundation model, anatomix, to derive fine-grained, per-voxel semantic representations that are consistent across volumes and further employ off-the-shelf segmentation models to obtain coarse anatomical identities. Together, these representations drive a GPU-accelerated iterative registration solver (FireANTs) in a hybrid multistage framework: the first stage estimates alignment from dense multi-channel features, after which a second refines the deformation using both anatomix- and segmentation-based losses. Lastly, because registration should not introduce non-biological tumor volume changes across time, we develop lesion-specific, component-wise volume preservation schemes. Without any task-specific training, our system placed first on the PSMAReg Challenge leaderboard. Code and interactive visualizations are available at https://www.neeldey.com/reps-for-reg.

Whole-body Positron Emission Tomography (PET) registration is essential for multi-parametric tumor characterization and assessment of metastatic disease progression. In deep learning-based deformable registration, the dense displacement field (DDF) regularizer is crucial for stabilizing optimization and preventing unrealistic deformations in large 3D volumes. A key challenge in whole-body deformable registration is anatomical heterogeneity, rigid structures (e.g., bones) should undergo stronger regularization, whereas soft tissues require more flexible deformation and weaker constraints. In this work, we propose a simple yet effective CT-guided spatially-varying regularization strategy for whole-body cross-tracer deformable PET registration. The key idea is to use the paired CT volume from the PET/CT acquisition to construct a voxel-wise regularization map for the DDF, replacing the conventional single global regularization weight. This yields anatomy-adaptive regularization strength across rigid and soft tissues. The proposed method is evaluated on a real clinical cross-tracer PET/CT dataset of 296 patients involving 18F-PSMA and 18F-FDG, showing that the proposed method achieves statistically significant improvements over weakly-supervised registration baseline in both whole-body registration performance and organ-wise alignment.

Dose accumulation is increasingly important in adaptive radiation therapy and reirradiation, but its clinical validity depends on the performance of deformable image registration (DIR). Reirradiation of brain metastases (BMs) with stereotactic radiosurgery (SRS) provides a controlled but clinically meaningful DIR test case: intra-subject brain deformation is usually limited after rigid alignment, yet recurrent lesions can undergo substantial local shape and volume changes that rigid registration cannot capture and can affect dose accumulation. We benchmarked a wide range of learning-based and optimization-based DIR methods on 87 manually screened longitudinal contrast-enhanced T1-weighted MRI lesion pairs from an institutional BM SRS retreatment cohort. Learning-based methods pretrained on healthy-brain MRI were evaluated zero-shot and after instance-specific optimization (ISO) or tumor-proximity target-specific optimization (TSO). Registration was assessed using lesion overlap (Dice), surface distance metrics (HD95 and sASD), target-volume recovery, and runtime and memory. Pretrained learning-based methods showed variable zero-shot performance, while ISO/TSO improved all tested learning-based families. However, optimization-based methods remained the best-performing approach while maintaining reasonable runtime. These findings suggest that even state-of-the-art DIR methods do not yet provide sufficiently accurate and consistent registration for unmonitored use in brain metastasis reirradiation dose accumulation. Because accurate registration is a prerequisite for deformable dose accumulation, clinical application will require case-level quality control and direct assessment of how registration uncertainty affects downstream dose metrics.