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It is clinically crucial and potentially very beneficial to be able to analyze and model directly the spatial distributions of cells in histopathology whole slide images (WSI). However, most existing WSI datasets lack cell-level annotations, owing to the extremely high cost over giga-pixel images. Thus, it remains an open question whether deep learning models can directly and effectively analyze WSIs from the semantic aspect of cell distributions. In this work, we construct a large-scale WSI dataset with more than 5 billion cell-level annotations, termed WSI-Cell5B, and a novel hierarchical Cell Cloud Transformer (CCFormer) to tackle these challenges. WSI-Cell5B is based on 6,998 WSIs of 11 cancers from The Cancer Genome Atlas Program, and all WSIs are annotated per cell by coordinates and types. To the best of our knowledge, WSI-Cell5B is the first WSI-level large-scale dataset integrating cell-level annotations. On the other hand, CCFormer formulates the collection of cells in each WSI as a cell cloud and models cell spatial distribution. Specifically, Neighboring Information Embedding (NIE) is proposed to characterize the distribution of cells within the neighborhood of each cell, and a novel Hierarchical Spatial Perception (HSP) module is proposed to learn the spatial relationship among cells in a bottom-up manner. The clinical analysis indicates that WSI-Cell5B can be used to design clinical evaluation metrics based on counting cells that effectively assess the survival risk of patients. Extensive experiments on survival prediction and cancer staging show that learning from cell spatial distribution alone can already achieve state-of-the-art (SOTA) performance, i.e., CCFormer strongly outperforms other competing methods.

Histopathology plays a critical role in medical diagnostics, with whole slide images (WSIs) offering valuable insights that directly influence clinical decision-making. However, the large size and complexity of WSIs may pose significant challenges for deep learning models, in both computational efficiency and effective representation learning. In this work, we introduce Pixel-Mamba, a novel deep learning architecture designed to efficiently handle gigapixel WSIs. Pixel-Mamba leverages the Mamba module, a state-space model (SSM) with linear memory complexity, and incorporates local inductive biases through progressively expanding tokens, akin to convolutional neural networks. This enables Pixel-Mamba to hierarchically combine both local and global information while efficiently addressing computational challenges. Remarkably, Pixel-Mamba achieves or even surpasses the quantitative performance of state-of-the-art (SOTA) foundation models that were pretrained on millions of WSIs or WSI-text pairs, in a range of tumor staging and survival analysis tasks, {\bf even without requiring any pathology-specific pretraining}. Extensive experiments demonstrate the efficacy of Pixel-Mamba as a powerful and efficient framework for end-to-end WSI analysis.

In the radiation therapy of nasopharyngeal carcinoma (NPC), clinicians typically delineate the gross tumor volume (GTV) using non-contrast planning computed tomography to ensure accurate radiation dose delivery. However, the low contrast between tumors and adjacent normal tissues necessitates that radiation oncologists manually delineate the tumors, often relying on diagnostic MRI for guidance. % In this study, we propose a novel approach to directly segment NPC gross tumors on non-contrast planning CT images, circumventing potential registration errors when aligning MRI or MRI-derived tumor masks to planning CT. To address the low contrast issues between tumors and adjacent normal structures in planning CT, we introduce a 3D Semantic Asymmetry Tumor segmentation (SATs) method. Specifically, we posit that a healthy nasopharyngeal region is characteristically bilaterally symmetric, whereas the emergence of nasopharyngeal carcinoma disrupts this symmetry. Then, we propose a Siamese contrastive learning segmentation framework that minimizes the voxel-wise distance between original and flipped areas without tumor and encourages a larger distance between original and flipped areas with tumor. Thus, our approach enhances the sensitivity of features to semantic asymmetries. % Extensive experiments demonstrate that the proposed SATs achieves the leading NPC GTV segmentation performance in both internal and external testing, \emph{e.g.}, with at least 2\% absolute Dice score improvement and 12\% average distance error reduction when compared to other state-of-the-art methods in the external testing.

Deep segmentation networks achieve high performance when trained on specific datasets. However, in clinical practice, it is often desirable that pretrained segmentation models can be dynamically extended to enable segmenting new organs without access to previous training datasets or without training from scratch. This would ensure a much more efficient model development and deployment paradigm accounting for the patient privacy and data storage issues. This clinically preferred process can be viewed as a continual semantic segmentation (CSS) problem. Previous CSS works would either experience catastrophic forgetting or lead to unaffordable memory costs as models expand. In this work, we propose a new continual whole-body organ segmentation model with light-weighted low-rank adaptation (LoRA). We first train and freeze a pyramid vision transformer (PVT) base segmentation model on the initial task, then continually add light-weighted trainable LoRA parameters to the frozen model for each new learning task. Through a holistically exploration of the architecture modification, we identify three most important layers (i.e., patch-embedding, multi-head attention and feed forward layers) that are critical in adapting to the new segmentation tasks, while retaining the majority of the pretrained parameters fixed. Our proposed model continually segments new organs without catastrophic forgetting and meanwhile maintaining a low parameter increasing rate. Continually trained and tested on four datasets covering different body parts of a total of 121 organs, results show that our model achieves high segmentation accuracy, closely reaching the PVT and nnUNet upper bounds, and significantly outperforms other regularization-based CSS methods. When comparing to the leading architecture-based CSS method, our model has a substantial lower parameter increasing rate while achieving comparable performance., Comment: Accepted by Medical Image Computing and Computer Assisted Intervention -- MICCAI 2024

Survival analysis using pathology images poses a considerable challenge, as it requires the localization of relevant information from the multitude of tiles within whole slide images (WSIs). Current methods typically resort to a two-stage approach, where a pre-trained network extracts features from tiles, which are then used by survival models. This process, however, does not optimize the survival models in an end-to-end manner, and the pre-extracted features may not be ideally suited for survival prediction. To address this limitation, we present a novel end-to-end Visual Prompt Tuning framework for survival analysis, named VPTSurv. VPTSurv refines feature embeddings through an efficient encoder-decoder framework. The encoder remains fixed while the framework introduces tunable visual prompts and adaptors, thus permitting end-to-end training specifically for survival prediction by optimizing only the lightweight adaptors and the decoder. Moreover, the versatile VPTSurv framework accommodates multi-source information as prompts, thereby enriching the survival model. VPTSurv achieves substantial increases of 8.7% and 12.5% in the C-index on two immunohistochemical pathology image datasets. These significant improvements highlight the transformative potential of the end-to-end VPT framework over traditional two-stage methods.

Lymph node (LN) assessment is a critical, indispensable yet very challenging task in the routine clinical workflow of radiology and oncology. Accurate LN analysis is essential for cancer diagnosis, staging, and treatment planning. Finding scatteredly distributed, low-contrast clinically relevant LNs in 3D CT is difficult even for experienced physicians under high inter-observer variations. Previous automatic LN detection works typically yield limited recall and high false positives (FPs) due to adjacent anatomies with similar image intensities, shapes, or textures (vessels, muscles, esophagus, etc). In this work, we propose a new LN DEtection TRansformer, named LN-DETR, to achieve more accurate performance. By enhancing the 2D backbone with a multi-scale 2.5D feature fusion to incorporate 3D context explicitly, more importantly, we make two main contributions to improve the representation quality of LN queries. 1) Considering that LN boundaries are often unclear, an IoU prediction head and a location debiased query selection are proposed to select LN queries of higher localization accuracy as the decoder query's initialization. 2) To reduce FPs, query contrastive learning is employed to explicitly reinforce LN queries towards their best-matched ground-truth queries over unmatched query predictions. Trained and tested on 3D CT scans of 1067 patients (with 10,000+ labeled LNs) via combining seven LN datasets from different body parts (neck, chest, and abdomen) and pathologies/cancers, our method significantly improves the performance of previous leading methods by > 4-5% average recall at the same FP rates in both internal and external testing. We further evaluate on the universal lesion detection task using NIH DeepLesion benchmark, and our method achieves the top performance of 88.46% averaged recall across 0.5 to 4 FPs per image, compared with other leading reported results., Comment: Technical report

Segment anything model (SAM) demonstrates strong generalization ability on natural image segmentation. However, its direct adaptation in medical image segmentation tasks shows significant performance drops. It also requires an excessive number of prompt points to obtain a reasonable accuracy. Although quite a few studies explore adapting SAM into medical image volumes, the efficiency of 2D adaptation methods is unsatisfactory and 3D adaptation methods are only capable of segmenting specific organs/tumors. In this work, we propose a comprehensive and scalable 3D SAM model for whole-body CT segmentation, named CT-SAM3D. Instead of adapting SAM, we propose a 3D promptable segmentation model using a (nearly) fully labeled CT dataset. To train CT-SAM3D effectively, ensuring the model's accurate responses to higher-dimensional spatial prompts is crucial, and 3D patch-wise training is required due to GPU memory constraints. Therefore, we propose two key technical developments: 1) a progressively and spatially aligned prompt encoding method to effectively encode click prompts in local 3D space; and 2) a cross-patch prompt scheme to capture more 3D spatial context, which is beneficial for reducing the editing workloads when interactively prompting on large organs. CT-SAM3D is trained using a curated dataset of 1204 CT scans containing 107 whole-body anatomies and extensively validated using five datasets, achieving significantly better results against all previous SAM-derived models. Code, data, and our 3D interactive segmentation tool with quasi-real-time responses are available at https://github.com/alibaba-damo-academy/ct-sam3d., Comment: Accepted by AAAI 2025

Establishing dense anatomical correspondence across distinct imaging modalities is a foundational yet challenging procedure for numerous medical image analysis studies and image-guided radiotherapy. Existing multi-modality image registration algorithms rely on statistical-based similarity measures or local structural image representations. However, the former is sensitive to locally varying noise, while the latter is not discriminative enough to cope with complex anatomical structures in multimodal scans, causing ambiguity in determining the anatomical correspondence across scans with different modalities. In this paper, we propose a modality-agnostic structural representation learning method, which leverages Deep Neighbourhood Self-similarity (DNS) and anatomy-aware contrastive learning to learn discriminative and contrast-invariance deep structural image representations (DSIR) without the need for anatomical delineations or pre-aligned training images. We evaluate our method on multiphase CT, abdomen MR-CT, and brain MR T1w-T2w registration. Comprehensive results demonstrate that our method is superior to the conventional local structural representation and statistical-based similarity measures in terms of discriminability and accuracy., Comment: Accepted by CVPR2024

Finding abnormal lymph nodes in radiological images is highly important for various medical tasks such as cancer metastasis staging and radiotherapy planning. Lymph nodes (LNs) are small glands scattered throughout the body. They are grouped or defined to various LN stations according to their anatomical locations. The CT imaging appearance and context of LNs in different stations vary significantly, posing challenges for automated detection, especially for pathological LNs. Motivated by this observation, we propose a novel end-to-end framework to improve LN detection performance by leveraging their station information. We design a multi-head detector and make each head focus on differentiating the LN and non-LN structures of certain stations. Pseudo station labels are generated by an LN station classifier as a form of multi-task learning during training, so we do not need another explicit LN station prediction model during inference. Our algorithm is evaluated on 82 patients with lung cancer and 91 patients with esophageal cancer. The proposed implicit station stratification method improves the detection sensitivity of thoracic lymph nodes from 65.1% to 71.4% and from 80.3% to 85.5% at 2 false positives per patient on the two datasets, respectively, which significantly outperforms various existing state-of-the-art baseline techniques such as nnUNet, nnDetection and LENS.

Estimating displacement vector field via a cost volume computed in the feature space has shown great success in image registration, but it suffers excessive computation burdens. Moreover, existing feature descriptors only extract local features incapable of representing the global semantic information, which is especially important for solving large transformations. To address the discussed issues, we propose SAMConvex, a fast coarse-to-fine discrete optimization method for CT registration that includes a decoupled convex optimization procedure to obtain deformation fields based on a self-supervised anatomical embedding (SAM) feature extractor that captures both local and global information. To be specific, SAMConvex extracts per-voxel features and builds 6D correlation volumes based on SAM features, and iteratively updates a flow field by performing lookups on the correlation volumes with a coarse-to-fine scheme. SAMConvex outperforms the state-of-the-art learning-based methods and optimization-based methods over two inter-patient registration datasets (Abdomen CT and HeadNeck CT) and one intra-patient registration dataset (Lung CT). Moreover, as an optimization-based method, SAMConvex only takes $\sim2$s ($\sim5s$ with instance optimization) for one paired images.

Radiotherapists require accurate registration of MR/CT images to effectively use information from both modalities. In a typical registration pipeline, rigid or affine transformations are applied to roughly align the fixed and moving images before proceeding with the deformation step. While recent learning-based methods have shown promising results in the rigid/affine step, these methods often require images with similar field-of-view (FOV) for successful alignment. As a result, aligning images with different FOVs remains a challenging task. Self-supervised landmark detection methods like self-supervised Anatomical eMbedding (SAM) have emerged as a useful tool for mapping and cropping images to similar FOVs. However, these methods are currently limited to intra-modality use only. To address this limitation and enable cross-modality matching, we propose a new approach called Cross-SAM. Our approach utilizes a novel iterative process that alternates between embedding learning and CT-MRI registration. We start by applying aggressive contrast augmentation on both CT and MRI images to train a SAM model. We then use this SAM to identify corresponding regions on paired images using robust grid-points matching, followed by a point-set based affine/rigid registration, and a deformable fine-tuning step to produce registered paired images. We use these registered pairs to enhance the matching ability of SAM, which is then processed iteratively. We use the final model for cross-modality matching tasks. We evaluated our approach on two CT-MRI affine registration datasets and found that Cross-SAM achieved robust affine registration on both datasets, significantly outperforming other methods and achieving state-of-the-art performance.

Intrathoracic airway segmentation in computed tomography (CT) is a prerequisite for various respiratory disease analyses such as chronic obstructive pulmonary disease (COPD), asthma and lung cancer. Unlike other organs with simpler shapes or topology, the airway's complex tree structure imposes an unbearable burden to generate the "ground truth" label (up to 7 or 3 hours of manual or semi-automatic annotation on each case). Most of the existing airway datasets are incompletely labeled/annotated, thus limiting the completeness of computer-segmented airway. In this paper, we propose a new anatomy-aware multi-class airway segmentation method enhanced by topology-guided iterative self-learning. Based on the natural airway anatomy, we formulate a simple yet highly effective anatomy-aware multi-class segmentation task to intuitively handle the severe intra-class imbalance of the airway. To solve the incomplete labeling issue, we propose a tailored self-iterative learning scheme to segment toward the complete airway tree. For generating pseudo-labels to achieve higher sensitivity , we introduce a novel breakage attention map and design a topology-guided pseudo-label refinement method by iteratively connecting breaking branches commonly existed from initial pseudo-labels. Extensive experiments have been conducted on four datasets including two public challenges. The proposed method ranked 1st in both EXACT'09 challenge using average score and ATM'22 challenge on weighted average score. In a public BAS dataset and a private lung cancer dataset, our method significantly improves previous leading approaches by extracting at least (absolute) 7.5% more detected tree length and 4.0% more tree branches, while maintaining similar precision.

Open international challenges are becoming the de facto standard for assessing computer vision and image analysis algorithms. In recent years, new methods have extended the reach of pulmonary airway segmentation that is closer to the limit of image resolution. Since EXACT'09 pulmonary airway segmentation, limited effort has been directed to quantitative comparison of newly emerged algorithms driven by the maturity of deep learning based approaches and clinical drive for resolving finer details of distal airways for early intervention of pulmonary diseases. Thus far, public annotated datasets are extremely limited, hindering the development of data-driven methods and detailed performance evaluation of new algorithms. To provide a benchmark for the medical imaging community, we organized the Multi-site, Multi-domain Airway Tree Modeling (ATM'22), which was held as an official challenge event during the MICCAI 2022 conference. ATM'22 provides large-scale CT scans with detailed pulmonary airway annotation, including 500 CT scans (300 for training, 50 for validation, and 150 for testing). The dataset was collected from different sites and it further included a portion of noisy COVID-19 CTs with ground-glass opacity and consolidation. Twenty-three teams participated in the entire phase of the challenge and the algorithms for the top ten teams are reviewed in this paper. Quantitative and qualitative results revealed that deep learning models embedded with the topological continuity enhancement achieved superior performance in general. ATM'22 challenge holds as an open-call design, the training data and the gold standard evaluation are available upon successful registration via its homepage., Comment: 32 pages, 16 figures. Homepage: https://atm22.grand-challenge.org/. Submitted

Deep learning empowers the mainstream medical image segmentation methods. Nevertheless current deep segmentation approaches are not capable of efficiently and effectively adapting and updating the trained models when new incremental segmentation classes (along with new training datasets or not) are required to be added. In real clinical environment, it can be preferred that segmentation models could be dynamically extended to segment new organs/tumors without the (re-)access to previous training datasets due to obstacles of patient privacy and data storage. This process can be viewed as a continual semantic segmentation (CSS) problem, being understudied for multi-organ segmentation. In this work, we propose a new architectural CSS learning framework to learn a single deep segmentation model for segmenting a total of 143 whole-body organs. Using the encoder/decoder network structure, we demonstrate that a continually-trained then frozen encoder coupled with incrementally-added decoders can extract and preserve sufficiently representative image features for new classes to be subsequently and validly segmented. To maintain a single network model complexity, we trim each decoder progressively using neural architecture search and teacher-student based knowledge distillation. To incorporate with both healthy and pathological organs appearing in different datasets, a novel anomaly-aware and confidence learning module is proposed to merge the overlapped organ predictions, originated from different decoders. Trained and validated on 3D CT scans of 2500+ patients from four datasets, our single network can segment total 143 whole-body organs with very high accuracy, closely reaching the upper bound performance level by training four separate segmentation models (i.e., one model per dataset/task).

Deep learning has been widely used in medical image segmentation and other aspects. However, the performance of existing medical image segmentation models has been limited by the challenge of obtaining sufficient high-quality labeled data due to the prohibitive data annotation cost. To alleviate this limitation, we propose a new text-augmented medical image segmentation model LViT (Language meets Vision Transformer). In our LViT model, medical text annotation is incorporated to compensate for the quality deficiency in image data. In addition, the text information can guide to generate pseudo labels of improved quality in the semi-supervised learning. We also propose an Exponential Pseudo label Iteration mechanism (EPI) to help the Pixel-Level Attention Module (PLAM) preserve local image features in semi-supervised LViT setting. In our model, LV (Language-Vision) loss is designed to supervise the training of unlabeled images using text information directly. For evaluation, we construct three multimodal medical segmentation datasets (image + text) containing X-rays and CT images. Experimental results show that our proposed LViT has superior segmentation performance in both fully-supervised and semi-supervised setting. The code and datasets are available at https://github.com/HUANGLIZI/LViT., Comment: Accepted by IEEE Transactions on Medical Imaging (TMI)

Accurate organ at risk (OAR) segmentation is critical to reduce the radiotherapy post-treatment complications. Consensus guidelines recommend a set of more than 40 OARs in the head and neck (H&N) region, however, due to the predictable prohibitive labor-cost of this task, most institutions choose a substantially simplified protocol by delineating a smaller subset of OARs and neglecting the dose distributions associated with other OARs. In this work we propose a novel, automated and highly effective stratified OAR segmentation (SOARS) system using deep learning to precisely delineate a comprehensive set of 42 H&N OARs. SOARS stratifies 42 OARs into anchor, mid-level, and small & hard subcategories, with specifically derived neural network architectures for each category by neural architecture search (NAS) principles. We built SOARS models using 176 training patients in an internal institution and independently evaluated on 1327 external patients across six different institutions. It consistently outperformed other state-of-the-art methods by at least 3-5% in Dice score for each institutional evaluation (up to 36% relative error reduction in other metrics). More importantly, extensive multi-user studies evidently demonstrated that 98% of the SOARS predictions need only very minor or no revisions for direct clinical acceptance (saving 90% radiation oncologists workload), and their segmentation and dosimetric accuracy are within or smaller than the inter-user variation. These findings confirmed the strong clinical applicability of SOARS for the OAR delineation process in H&N cancer radiotherapy workflows, with improved efficiency, comprehensiveness, and quality.

Background: The current clinical workflow for esophageal gross tumor volume (GTV) contouring relies on manual delineation of high labor-costs and interuser variability. Purpose: To validate the clinical applicability of a deep learning (DL) multi-modality esophageal GTV contouring model, developed at 1 institution whereas tested at multiple ones. Methods and Materials: We collected 606 esophageal cancer patients from four institutions. 252 institution-1 patients had a treatment planning-CT (pCT) and a pair of diagnostic FDG-PETCT; 354 patients from other 3 institutions had only pCT. A two-streamed DL model for GTV segmentation was developed using pCT and PETCT scans of a 148 patient institution-1 subset. This built model had the flexibility of segmenting GTVs via only pCT or pCT+PETCT combined. For independent evaluation, the rest 104 institution-1 patients behaved as unseen internal testing, and 354 institutions 2-4 patients were used for external testing. We evaluated manual revision degrees by human experts to assess the contour-editing effort. The performance of the deep model was compared against 4 radiation oncologists in a multiuser study with 20 random external patients. Contouring accuracy and time were recorded for the pre-and post-DL assisted delineation process. Results: Our model achieved high segmentation accuracy in internal testing (mean Dice score: 0.81 using pCT and 0.83 using pCT+PET) and generalized well to external evaluation (mean DSC: 0.80). Expert assessment showed that the predicted contours of 88% patients need only minor or no revision. In multi-user evaluation, with the assistance of a deep model, inter-observer variation and required contouring time were reduced by 37.6% and 48.0%, respectively. Conclusions: Deep learning predicted GTV contours were in close agreement with the ground truth and could be adopted clinically with mostly minor or no changes., Comment: 36 pages, 10 figures

In this work, we introduce a fast and accurate method for unsupervised 3D medical image registration. This work is built on top of a recent algorithm SAM, which is capable of computing dense anatomical/semantic correspondences between two images at the pixel level. Our method is named SAME, which breaks down image registration into three steps: affine transformation, coarse deformation, and deep deformable registration. Using SAM embeddings, we enhance these steps by finding more coherent correspondences, and providing features and a loss function with better semantic guidance. We collect a multi-phase chest computed tomography dataset with 35 annotated organs for each patient and conduct inter-subject registration for quantitative evaluation. Results show that SAME outperforms widely-used traditional registration techniques (Elastix FFD, ANTs SyN) and learning based VoxelMorph method by at least 4.7% and 2.7% in Dice scores for two separate tasks of within-contrast-phase and across-contrast-phase registration, respectively. SAME achieves the comparable performance to the best traditional registration method, DEEDS (from our evaluation), while being orders of magnitude faster (from 45 seconds to 1.2 seconds).

Lymph node station (LNS) delineation from computed tomography (CT) scans is an indispensable step in radiation oncology workflow. High inter-user variabilities across oncologists and prohibitive laboring costs motivated the automated approach. Previous works exploit anatomical priors to infer LNS based on predefined ad-hoc margins. However, without voxel-level supervision, the performance is severely limited. LNS is highly context-dependent - LNS boundaries are constrained by anatomical organs - we formulate it as a deep spatial and contextual parsing problem via encoded anatomical organs. This permits the deep network to better learn from both CT appearance and organ context. We develop a stratified referencing organ segmentation protocol that divides the organs into anchor and non-anchor categories and uses the former's predictions to guide the later segmentation. We further develop an auto-search module to identify the key organs that opt for the optimal LNS parsing performance. Extensive four-fold cross-validation experiments on a dataset of 98 esophageal cancer patients (with the most comprehensive set of 12 LNSs + 22 organs in thoracic region to date) are conducted. Our LNS parsing model produces significant performance improvements, with an average Dice score of 81.1% +/- 6.1%, which is 5.0% and 19.2% higher over the pure CT-based deep model and the previous representative approach, respectively.

3D delineation of anatomical structures is a cardinal goal in medical imaging analysis. Prior to deep learning, statistical shape models that imposed anatomical constraints and produced high quality surfaces were a core technology. Prior to deep learning, statistical shape models that imposed anatomical constraints and produced high quality surfaces were a core technology. Today fully-convolutional networks (FCNs), while dominant, do not offer these capabilities. We present deep implicit statistical shape models (DISSMs), a new approach to delineation that marries the representation power of convolutional neural networks (CNNs) with the robustness of SSMs. DISSMs use a deep implicit surface representation to produce a compact and descriptive shape latent space that permits statistical models of anatomical variance. To reliably fit anatomically plausible shapes to an image, we introduce a novel rigid and non-rigid pose estimation pipeline that is modelled as a Markov decision process(MDP). We outline a training regime that includes inverted episodic training and a deep realization of marginal space learning (MSL). Intra-dataset experiments on the task of pathological liver segmentation demonstrate that DISSMs can perform more robustly than three leading FCN models, including nnU-Net: reducing the mean Hausdorff distance (HD) by 7.7-14.3mm and improving the worst case Dice-Sorensen coefficient (DSC) by 1.2-2.3%. More critically, cross-dataset experiments on a dataset directly reflecting clinical deployment scenarios demonstrate that DISSMs improve the mean DSC and HD by 3.5-5.9% and 12.3-24.5mm, respectively, and the worst-case DSC by 5.4-7.3%. These improvements are over and above any benefits from representing delineations with high-quality surface.

Radiological images such as computed tomography (CT) and X-rays render anatomy with intrinsic structures. Being able to reliably locate the same anatomical structure across varying images is a fundamental task in medical image analysis. In principle it is possible to use landmark detection or semantic segmentation for this task, but to work well these require large numbers of labeled data for each anatomical structure and sub-structure of interest. A more universal approach would learn the intrinsic structure from unlabeled images. We introduce such an approach, called Self-supervised Anatomical eMbedding (SAM). SAM generates semantic embeddings for each image pixel that describes its anatomical location or body part. To produce such embeddings, we propose a pixel-level contrastive learning framework. A coarse-to-fine strategy ensures both global and local anatomical information are encoded. Negative sample selection strategies are designed to enhance the embedding's discriminability. Using SAM, one can label any point of interest on a template image and then locate the same body part in other images by simple nearest neighbor searching. We demonstrate the effectiveness of SAM in multiple tasks with 2D and 3D image modalities. On a chest CT dataset with 19 landmarks, SAM outperforms widely-used registration algorithms while only taking 0.23 seconds for inference. On two X-ray datasets, SAM, with only one labeled template image, surpasses supervised methods trained on 50 labeled images. We also apply SAM on whole-body follow-up lesion matching in CT and obtain an accuracy of 91%. SAM can also be applied for improving image registration and initializing CNN weights., Comment: code: https://github.com/alibaba-damo-academy/self-supervised-anatomical-embedding-v2; IEEE Trans on Medical Imaging: https://ieeexplore.ieee.org/document/9760421

Large-scale datasets with high-quality labels are desired for training accurate deep learning models. However, due to the annotation cost, datasets in medical imaging are often either partially-labeled or small. For example, DeepLesion is such a large-scale CT image dataset with lesions of various types, but it also has many unlabeled lesions (missing annotations). When training a lesion detector on a partially-labeled dataset, the missing annotations will generate incorrect negative signals and degrade the performance. Besides DeepLesion, there are several small single-type datasets, such as LUNA for lung nodules and LiTS for liver tumors. These datasets have heterogeneous label scopes, i.e., different lesion types are labeled in different datasets with other types ignored. In this work, we aim to develop a universal lesion detection algorithm to detect a variety of lesions. The problem of heterogeneous and partial labels is tackled. First, we build a simple yet effective lesion detection framework named Lesion ENSemble (LENS). LENS can efficiently learn from multiple heterogeneous lesion datasets in a multi-task fashion and leverage their synergy by proposal fusion. Next, we propose strategies to mine missing annotations from partially-labeled datasets by exploiting clinical prior knowledge and cross-dataset knowledge transfer. Finally, we train our framework on four public lesion datasets and evaluate it on 800 manually-labeled sub-volumes in DeepLesion. Our method brings a relative improvement of 49% compared to the current state-of-the-art approach in the metric of average sensitivity. We have publicly released our manual 3D annotations of DeepLesion in https://github.com/viggin/DeepLesion_manual_test_set., Comment: IEEE Trans on Medical Imaging. Annotation and evaluation code in https://github.com/viggin/DeepLesion_manual_test_set

Determining the spread of GTV$_{LN}$ is essential in defining the respective resection or irradiating regions for the downstream workflows of surgical resection and radiotherapy for many cancers. Different from the more common enlarged lymph node (LN), GTV$_{LN}$ also includes smaller ones if associated with high positron emission tomography signals and/or any metastasis signs in CT. This is a daunting task. In this work, we propose a unified LN appearance and inter-LN relationship learning framework to detect the true GTV$_{LN}$. This is motivated by the prior clinical knowledge that LNs form a connected lymphatic system, and the spread of cancer cells among LNs often follows certain pathways. Specifically, we first utilize a 3D convolutional neural network with ROI-pooling to extract the GTV$_{LN}$'s instance-wise appearance features. Next, we introduce a graph neural network to further model the inter-LN relationships where the global LN-tumor spatial priors are included in the learning process. This leads to an end-to-end trainable network to detect by classifying GTV$_{LN}$. We operate our model on a set of GTV$_{LN}$ candidates generated by a preliminary 1st-stage method, which has a sensitivity of $>85\%$ at the cost of high false positive (FP) ($>15$ FPs per patient). We validate our approach on a radiotherapy dataset with 142 paired PET/RTCT scans containing the chest and upper abdominal body parts. The proposed method significantly improves over the state-of-the-art (SOTA) LN classification method by $5.5\%$ and $13.1\%$ in F1 score and the averaged sensitivity value at $2, 3, 4, 6$ FPs per patient, respectively., Comment: Accepted to MICCAI 2020

Finding, identifying and segmenting suspicious cancer metastasized lymph nodes from 3D multi-modality imaging is a clinical task of paramount importance. In radiotherapy, they are referred to as Lymph Node Gross Tumor Volume (GTVLN). Determining and delineating the spread of GTVLN is essential in defining the corresponding resection and irradiating regions for the downstream workflows of surgical resection and radiotherapy of various cancers. In this work, we propose an effective distance-based gating approach to simulate and simplify the high-level reasoning protocols conducted by radiation oncologists, in a divide-and-conquer manner. GTVLN is divided into two subgroups of tumor-proximal and tumor-distal, respectively, by means of binary or soft distance gating. This is motivated by the observation that each category can have distinct though overlapping distributions of appearance, size and other LN characteristics. A novel multi-branch detection-by-segmentation network is trained with each branch specializing on learning one GTVLN category features, and outputs from multi-branch are fused in inference. The proposed method is evaluated on an in-house dataset of $141$ esophageal cancer patients with both PET and CT imaging modalities. Our results validate significant improvements on the mean recall from $72.5\%$ to $78.2\%$, as compared to previous state-of-the-art work. The highest achieved GTVLN recall of $82.5\%$ at $20\%$ precision is clinically relevant and valuable since human observers tend to have low sensitivity (around $80\%$ for the most experienced radiation oncologists, as reported by literature)., Comment: MICCAI2020

Accurate and automated tumor segmentation is highly desired since it has the great potential to increase the efficiency and reproducibility of computing more complete tumor measurements and imaging biomarkers, comparing to (often partial) human measurements. This is probably the only viable means to enable the large-scale clinical oncology patient studies that utilize medical imaging. Deep learning approaches have shown robust segmentation performances for certain types of tumors, e.g., brain tumors in MRI imaging, when a training dataset with plenty of pixel-level fully-annotated tumor images is available. However, more than often, we are facing the challenge that only (very) limited annotations are feasible to acquire, especially for hard tumors. Pancreatic ductal adenocarcinoma (PDAC) segmentation is one of the most challenging tumor segmentation tasks, yet critically important for clinical needs. Previous work on PDAC segmentation is limited to the moderate amounts of annotated patient images (n<300) from venous or venous+arterial phase CT scans. Based on a new self-learning framework, we propose to train the PDAC segmentation model using a much larger quantity of patients (n~=1,000), with a mix of annotated and un-annotated venous or multi-phase CT images. Pseudo annotations are generated by combining two teacher models with different PDAC segmentation specialties on unannotated images, and can be further refined by a teaching assistant model that identifies associated vessels around the pancreas. A student model is trained on both manual and pseudo annotated multi-phase images. Experiment results show that our proposed method provides an absolute improvement of 6.3% Dice score over the strong baseline of nnUNet trained on annotated images, achieving the performance (Dice = 0.71) similar to the inter-observer variability between radiologists., Comment: 10 pages, 2 figures; MICCAI 2020

Lesion detection is an important problem within medical imaging analysis. Most previous work focuses on detecting and segmenting a specialized category of lesions (e.g., lung nodules). However, in clinical practice, radiologists are responsible for finding all possible types of anomalies. The task of universal lesion detection (ULD) was proposed to address this challenge by detecting a large variety of lesions from the whole body. There are multiple heterogeneously labeled datasets with varying label completeness: DeepLesion, the largest dataset of 32,735 annotated lesions of various types, but with even more missing annotation instances; and several fully-labeled single-type lesion datasets, such as LUNA for lung nodules and LiTS for liver tumors. In this work, we propose a novel framework to leverage all these datasets together to improve the performance of ULD. First, we learn a multi-head multi-task lesion detector using all datasets and generate lesion proposals on DeepLesion. Second, missing annotations in DeepLesion are retrieved by a new method of embedding matching that exploits clinical prior knowledge. Last, we discover suspicious but unannotated lesions using knowledge transfer from single-type lesion detectors. In this way, reliable positive and negative regions are obtained from partially-labeled and unlabeled images, which are effectively utilized to train ULD. To assess the clinically realistic protocol of 3D volumetric ULD, we fully annotated 1071 CT sub-volumes in DeepLesion. Our method outperforms the current state-of-the-art approach by 29% in the metric of average sensitivity.

Finding and identifying scatteredly-distributed, small, and critically important objects in 3D oncology images is very challenging. We focus on the detection and segmentation of oncology-significant (or suspicious cancer metastasized) lymph nodes (OSLNs), which has not been studied before as a computational task. Determining and delineating the spread of OSLNs is essential in defining the corresponding resection/irradiating regions for the downstream workflows of surgical resection and radiotherapy of various cancers. For patients who are treated with radiotherapy, this task is performed by experienced radiation oncologists that involves high-level reasoning on whether LNs are metastasized, which is subject to high inter-observer variations. In this work, we propose a divide-and-conquer decision stratification approach that divides OSLNs into tumor-proximal and tumor-distal categories. This is motivated by the observation that each category has its own different underlying distributions in appearance, size and other characteristics. Two separate detection-by-segmentation networks are trained per category and fused. To further reduce false positives (FP), we present a novel global-local network (GLNet) that combines high-level lesion characteristics with features learned from localized 3D image patches. Our method is evaluated on a dataset of 141 esophageal cancer patients with PET and CT modalities (the largest to-date). Our results significantly improve the recall from $45\%$ to $67\%$ at $3$ FPs per patient as compared to previous state-of-the-art methods. The highest achieved OSLN recall of $0.828$ is clinically relevant and valuable., Comment: 14 pages, 4 Figures

Multi-modal image registration is a challenging problem that is also an important clinical task for many real applications and scenarios. As a first step in analysis, deformable registration among different image modalities is often required in order to provide complementary visual information. During registration, semantic information is key to match homologous points and pixels. Nevertheless, many conventional registration methods are incapable in capturing high-level semantic anatomical dense correspondences. In this work, we propose a novel multi-task learning system, JSSR, based on an end-to-end 3D convolutional neural network that is composed of a generator, a registration and a segmentation component. The system is optimized to satisfy the implicit constraints between different tasks in an unsupervised manner. It first synthesizes the source domain images into the target domain, then an intra-modal registration is applied on the synthesized images and target images. The segmentation module are then applied on the synthesized and target images, providing additional cues based on semantic correspondences. The supervision from another fully-annotated dataset is used to regularize the segmentation. We extensively evaluate JSSR on a large-scale medical image dataset containing 1,485 patient CT imaging studies of four different contrast phases (i.e., 5,940 3D CT scans with pathological livers) on the registration, segmentation and synthesis tasks. The performance is improved after joint training on the registration and segmentation tasks by 0.9% and 1.9% respectively compared to a highly competitive and accurate deep learning baseline. The registration also consistently outperforms conventional state-of-the-art multi-modal registration methods., Comment: accepted to ECCV 2020

OAR segmentation is a critical step in radiotherapy of head and neck (H&N) cancer, where inconsistencies across radiation oncologists and prohibitive labor costs motivate automated approaches. However, leading methods using standard fully convolutional network workflows that are challenged when the number of OARs becomes large, e.g. > 40. For such scenarios, insights can be gained from the stratification approaches seen in manual clinical OAR delineation. This is the goal of our work, where we introduce stratified organ at risk segmentation (SOARS), an approach that stratifies OARs into anchor, mid-level, and small & hard (S&H) categories. SOARS stratifies across two dimensions. The first dimension is that distinct processing pipelines are used for each OAR category. In particular, inspired by clinical practices, anchor OARs are used to guide the mid-level and S&H categories. The second dimension is that distinct network architectures are used to manage the significant contrast, size, and anatomy variations between different OARs. We use differentiable neural architecture search (NAS), allowing the network to choose among 2D, 3D or Pseudo-3D convolutions. Extensive 4-fold cross-validation on 142 H&N cancer patients with 42 manually labeled OARs, the most comprehensive OAR dataset to date, demonstrates that both pipeline- and NAS-stratification significantly improves quantitative performance over the state-of-the-art (from 69.52% to 73.68% in absolute Dice scores). Thus, SOARS provides a powerful and principled means to manage the highly complex segmentation space of OARs.

Hip and pelvic fractures are serious injuries with life-threatening complications. However, diagnostic errors of fractures in pelvic X-rays (PXRs) are very common, driving the demand for computer-aided diagnosis (CAD) solutions. A major challenge lies in the fact that fractures are localized patterns that require localized analyses. Unfortunately, the PXRs residing in hospital picture archiving and communication system do not typically specify region of interests. In this paper, we propose a two-stage hip and pelvic fracture detection method that executes localized fracture classification using weakly supervised ROI mining. The first stage uses a large capacity fully-convolutional network, i.e., deep with high levels of abstraction, in a multiple instance learning setting to automatically mine probable true positive and definite hard negative ROIs from the whole PXR in the training data. The second stage trains a smaller capacity model, i.e., shallower and more generalizable, with the mined ROIs to perform localized analyses to classify fractures. During inference, our method detects hip and pelvic fractures in one pass by chaining the probability outputs of the two stages together. We evaluate our method on 4 410 PXRs, reporting an area under the ROC curve value of 0.975, the highest among state-of-the-art fracture detection methods. Moreover, we show that our two-stage approach can perform comparably to human physicians (even outperforming emergency physicians and surgeons), in a preliminary reader study of 23 readers., Comment: MICCAI 2019 (early accept)

Gross tumor volume (GTV) segmentation is a critical step in esophageal cancer radiotherapy treatment planning. Inconsistencies across oncologists and prohibitive labor costs motivate automated approaches for this task. However, leading approaches are only applied to radiotherapy computed tomography (RTCT) images taken prior to treatment. This limits the performance as RTCT suffers from low contrast between the esophagus, tumor, and surrounding tissues. In this paper, we aim to exploit both RTCT and positron emission tomography (PET) imaging modalities to facilitate more accurate GTV segmentation. By utilizing PET, we emulate medical professionals who frequently delineate GTV boundaries through observation of the RTCT images obtained after prescribing radiotherapy and PET/CT images acquired earlier for cancer staging. To take advantage of both modalities, we present a two-stream chained segmentation approach that effectively fuses the CT and PET modalities via early and late 3D deep-network-based fusion. Furthermore, to effect the fusion and segmentation we propose a simple yet effective progressive semantically nested network (PSNN) model that outperforms more complicated models. Extensive 5-fold cross-validation on 110 esophageal cancer patients, the largest analysis to date, demonstrates that both the proposed two-stream chained segmentation pipeline and the PSNN model can significantly improve the quantitative performance over the previous state-of-the-art work by 11% in absolute Dice score (DSC) (from 0.654 to 0.764) and, at the same time, reducing the Hausdorff distance from 129 mm to 47 mm., Comment: MICCAI 2019 (early accept and oral presentation)

Clinical target volume (CTV) delineation from radiotherapy computed tomography (RTCT) images is used to define the treatment areas containing the gross tumor volume (GTV) and/or sub-clinical malignant disease for radiotherapy (RT). High intra- and inter-user variability makes this a particularly difficult task for esophageal cancer. This motivates automated solutions, which is the aim of our work. Because CTV delineation is highly context-dependent--it must encompass the GTV and regional lymph nodes (LNs) while also avoiding excessive exposure to the organs at risk (OARs)--we formulate it as a deep contextual appearance-based problem using encoded spatial contexts of these anatomical structures. This allows the deep network to better learn from and emulate the margin- and appearance-based delineation performed by human physicians. Additionally, we develop domain-specific data augmentation to inject robustness to our system. Finally, we show that a simple 3D progressive holistically nested network (PHNN), which avoids computationally heavy decoding paths while still aggregating features at different levels of context, can outperform more complicated networks. Cross-validated experiments on a dataset of 135 esophageal cancer patients demonstrate that our encoded spatial context approach can produce concrete performance improvements, with an average Dice score of 83.9% and an average surface distance of 4.2 mm, representing improvements of 3.8% and 2.4 mm, respectively, over the state-of-the-art approach., Comment: MICCAI 2019 (early accept)

Quantification of cerebral white matter hyperintensities (WMH) of presumed vascular origin is of key importance in many neurological research studies. Currently, measurements are often still obtained from manual segmentations on brain MR images, which is a laborious procedure. Automatic WMH segmentation methods exist, but a standardized comparison of the performance of such methods is lacking. We organized a scientific challenge, in which developers could evaluate their method on a standardized multi-center/-scanner image dataset, giving an objective comparison: the WMH Segmentation Challenge (https://wmh.isi.uu.nl/). Sixty T1+FLAIR images from three MR scanners were released with manual WMH segmentations for training. A test set of 110 images from five MR scanners was used for evaluation. Segmentation methods had to be containerized and submitted to the challenge organizers. Five evaluation metrics were used to rank the methods: (1) Dice similarity coefficient, (2) modified Hausdorff distance (95th percentile), (3) absolute log-transformed volume difference, (4) sensitivity for detecting individual lesions, and (5) F1-score for individual lesions. Additionally, methods were ranked on their inter-scanner robustness. Twenty participants submitted their method for evaluation. This paper provides a detailed analysis of the results. In brief, there is a cluster of four methods that rank significantly better than the other methods, with one clear winner. The inter-scanner robustness ranking shows that not all methods generalize to unseen scanners. The challenge remains open for future submissions and provides a public platform for method evaluation., Comment: Accepted for publication in IEEE Transactions on Medical Imaging

Data availability plays a critical role for the performance of deep learning systems. This challenge is especially acute within the medical image domain, particularly when pathologies are involved, due to two factors: 1) limited number of cases, and 2) large variations in location, scale, and appearance. In this work, we investigate whether augmenting a dataset with artificially generated lung nodules can improve the robustness of the progressive holistically nested network (P-HNN) model for pathological lung segmentation of CT scans. To achieve this goal, we develop a 3D generative adversarial network (GAN) that effectively learns lung nodule property distributions in 3D space. In order to embed the nodules within their background context, we condition the GAN based on a volume of interest whose central part containing the nodule has been erased. To further improve realism and blending with the background, we propose a novel multi-mask reconstruction loss. We train our method on over 1000 nodules from the LIDC dataset. Qualitative results demonstrate the effectiveness of our method compared to the state-of-art. We then use our GAN to generate simulated training images where nodules lie on the lung border, which are cases where the published P-HNN model struggles. Qualitative and quantitative results demonstrate that armed with these simulated images, the P-HNN model learns to better segment lung regions under these challenging situations. As a result, our system provides a promising means to help overcome the data paucity that commonly afflicts medical imaging., Comment: MICCAI 2018

Segmentation and quantification of white matter hyperintensities (WMHs) are of great importance in studying and understanding various neurological and geriatric disorders. Although automatic methods have been proposed for WMH segmentation on magnetic resonance imaging (MRI), manual corrections are often necessary to achieve clinically practical results. Major challenges for WMH segmentation stem from their inhomogeneous MRI intensities, random location and size distributions, and MRI noise. The presence of other brain anatomies or diseases with enhanced intensities adds further difficulties. To cope with these challenges, we present a specifically designed fully convolutional neural network (FCN) with residual connections to segment WMHs by using combined T1 and fluid-attenuated inversion recovery (FLAIR) images. Our customized FCN is designed to be straightforward and generalizable, providing efficient end-to-end training due to its enhanced information propagation. We tested our method on the open WMH Segmentation Challenge MICCAI2017 dataset, and, despite our method's relative simplicity, results show that it performs amongst the leading techniques across five metrics. More importantly, our method achieves the best score for hausdorff distance and average volume difference in testing datasets from two MRI scanners that were not included in training, demonstrating better generalization ability of our proposed method over its competitors., Comment: IEEE International Symposium on Biomedical Imaging (ISBI)

Automatic pathological pulmonary lobe segmentation(PPLS) enables regional analyses of lung disease, a clinically important capability. Due to often incomplete lobe boundaries, PPLS is difficult even for experts, and most prior art requires inference from contextual information. To address this, we propose a novel PPLS method that couples deep learning with the random walker (RW) algorithm. We first employ the recent progressive holistically-nested network (P-HNN) model to identify potential lobar boundaries, then generate final segmentations using a RW that is seeded and weighted by the P-HNN output. We are the first to apply deep learning to PPLS. The advantages are independence from prior airway/vessel segmentations, increased robustness in diseased lungs, and methodological simplicity that does not sacrifice accuracy. Our method posts a high mean Jaccard score of 0.888$\pm$0.164 on a held-out set of 154 CT scans from lung-disease patients, while also significantly (p < 0.001) outperforming a state-of-the-art method.