Jinzuo Ye

Intraoperative Imaging-Guided Cancer Surgery: From Current Fluorescence Molecular Imaging Methods to Future Multi-Modality Imaging Technology

Cancer is a major threat to human health. Diagnosis and treatment using precision medicine is expected to be an effective method for preventing the initiation and progression of cancer. Although anatomical and functional imaging techniques such as radiography, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have played an important role for accurate preoperative diagnostics, for the most part these techniques cannot be applied intraoperatively. Optical molecular imaging is a promising technique that provides a high degree of sensitivity and specificity in tumor margin detection. Furthermore, existing clinical applications have proven that optical molecular imaging is a powerful intraoperative tool for guiding surgeons performing precision procedures, thus enabling radical resection and improved survival rates. However, detection depth limitation exists in optical molecular imaging methods and further breakthroughs from optical to multi-modality intraoperative imaging methods are needed to develop more extensive and comprehensive intraoperative applications. Here, we review the current intraoperative optical molecular imaging technologies, focusing on contrast agents and surgical navigation systems, and then discuss the future prospects of multi-modality imaging technology for intraoperative imaging-guided cancer surgery.

Use of Indocyanine Green for Detecting the Sentinel Lymph Node in Breast Cancer Patients: From Preclinical Evaluation to Clinical Validation

Assessment of the sentinel lymph node (SLN) in patients with early stage breast cancer is vital in selecting the appropriate surgical approach. However, the existing methods, including methylene blue and nuclides, possess low efficiency and effectiveness in mapping SLNs, and to a certain extent exert side effects during application. Indocyanine green (ICG), as a fluorescent dye, has been proved reliable usage in SLN detection by several other groups. In this paper, we introduce a novel surgical navigation system to detect SLN with ICG. This system contains two charge-coupled devices (CCD) to simultaneously capture real-time color and fluorescent video images through two different bands. During surgery, surgeons only need to follow the fluorescence display. In addition, the system saves data automatically during surgery enabling surgeons to find the registration point easily according to image recognition algorithms. To test our system, 5 mice and 10 rabbits were used for the preclinical setting and 22 breast cancer patients were utilized for the clinical evaluation in our experiments. The detection rate was 100% and an average of 2.7 SLNs was found in 22 patients. Our results show that the usage of our surgical navigation system with ICG to detect SLNs in breast cancer patients is technically feasible.

Fast and robust reconstruction for fluorescence molecular tomography via a sparsity adaptive subspace pursuit method

Fluorescence molecular tomography (FMT), as a promising imaging modality, can three-dimensionally locate the specific tumor position in small animals. However, it remains challenging for effective and robust reconstruction of fluorescent probe distribution in animals. In this paper, we present a novel method based on sparsity adaptive subspace pursuit (SASP) for FMT reconstruction. Some innovative strategies including subspace projection, the bottom-up sparsity adaptive approach, and backtracking technique are associated with the SASP method, which guarantees the accuracy, efficiency, and robustness for FMT reconstruction. Three numerical experiments based on a mouse-mimicking heterogeneous phantom have been performed to validate the feasibility of the SASP method. The results show that the proposed SASP method can achieve satisfactory source localization with a bias less than 1mm; the efficiency of the method is much faster than mainstream reconstruction methods; and this approach is robust even under quite ill-posed condition. Furthermore, we have applied this method to an in vivo mouse model, and the results demonstrate the feasibility of the practical FMT application with the SASP method.

Intraoperative Identification of Liver Cancer Microfoci Using a Targeted Near-Infrared Fluorescent Probe for Imaging-Guided Surgery

Difficulties in the highly sensitive detection of tumour microfoci represent a critical obstacle toward improved surgical intervention in liver cancer. Conventional preoperative imaging methods and surgeons’ subjective experience are limited by their inability to effectively detect tumour lesions measuring less than 2 mm; however, intraoperative fluorescence molecular imaging may overcome this limitation. Here, we synthesised an arginine-glycine-aspartic acid (RGD)-conjugated mesoporous silica nanoparticle (MSN) highly loaded with indocyanine green (ICG) dye that could accurately delineate liver cancer margins and provide excellent tumour-to-normal tissue contrast intraoperatively. The increased ICG loading capacity and tumour specificity enabled the identification of residual microtumours and satellite lesions measuring less than 1 mm in living mice. Histological analysis validated the sensitivity and accuracy of this approach. We believe this technique utilising a new fluorescent nanoprobe with intraoperative optical imaging may offer a more sensitive and accurate method for liver cancer resection guidance, resulting in better surgical outcomes.

Optical Molecular Imaging Frontiers in Oncology: The Pursuit of Accuracy and Sensitivity

Cutting-edge technologies in optical molecular imaging have ushered in new frontiers in cancer research, clinical translation, and medical practice, as evidenced by recent advances in optical multimodality imaging, Cerenkov luminescence imaging (CLI), and optical image-guided surgeries. New abilities allow in vivo cancer imaging with sensitivity and accuracy that are unprecedented in conventional imaging approaches. The visualization of cellular and molecular behaviors and events within tumors in living subjects is improving our deeper understanding of tumors at a systems level. These advances are being rapidly used to acquire tumor-to-tumor molecular heterogeneity, both dynamically and quantitatively, as well as to achieve more effective therapeutic interventions with the assistance of real-time imaging. In the era of molecular imaging, optical technologies hold great promise to facilitate the development of highly sensitive cancer diagnoses as well as personalized patient treatment—one of the ultimate goals of precision medicine.

A Novel Region Reconstruction Method for Fluorescence Molecular Tomography

Fluorescence molecular tomography (FMT) could exploit the distribution of fluorescent biomarkers that target tumors accurately and effectively, which enables noninvasive real-time 3-D visualization as well as quantitative analysis of small tumors in small animal studies in vivo. Due to the difficulties of reconstruction, continuous efforts are being made to find more practical and efficient approaches to accurately obtain the characteristics of fluorescent regions inside biological tissues. In this paper, we propose a region reconstruction method for FMT, which is defined as an L1-norm regularization piecewise constant level set approach. The proposed approach adopts a priori information including the sparsity of the fluorescent sources and the fluorescent contrast between the target and background. When the contrast of different fluorescent sources is low to a certain degree, our approach can simultaneously solve the detection and characterization problems for the reconstruction of FMT. To evaluate the performance of the region reconstruction method, numerical phantom experiments and in vivo bead-implanted mouse experiments were performed. The results suggested that the proposed region reconstruction method was able to reconstruct the features of the fluorescent regions accurately and effectively, and the proposed method was able to be feasibly adopted in in vivo application.

Reconstruction of fluorescence molecular tomography via a nonmonotone spectral projected gradient pursuit method

Abstract. Fluorescence molecular tomography (FMT) is a promising imaging technique in preclinical research, enabling three-dimensional location of the specific tumor position for small animal imaging. However, FMT presents a challenging inverse problem that is quite ill-posed and ill-conditioned. Thus, the reconstruction of FMT faces various challenges in its robustness and efficiency. We present an FMT reconstruction method based on nonmonotone spectral projected gradient pursuit (NSPGP) with l1-norm optimization. At each iteration, a spectral gradient-projection method approximately minimizes a least-squares problem with an explicit one-norm constraint. A nonmonotone line search strategy is utilized to get the appropriate updating direction, which guarantees global convergence. Additionally, the Barzilai–Borwein step length is applied to build the optimal step length, further improving the convergence speed of the proposed method. Several numerical simulation studies, including multisource cases as well as comparative analyses, have been performed to evaluate the performance of the proposed method. The results indicate that the proposed NSPGP method is able to ensure the accuracy, robustness, and efficiency of FMT reconstruction. Furthermore, an in vivo experiment based on a heterogeneous mouse model was conducted, and the results demonstrated that the proposed method held the potential for practical applications of FMT.

Comparison between the indocyanine green fluorescence and blue dye methods for sentinel lymph node biopsy using novel fluorescence image-guided resection equipment in different types of hospitals

Sentinel lymph node biopsy (SLNB) has become a standard of care to detect axillary lymph metastasis in early-stage breast cancer patients with clinically negative axillary lymph nodes. Current SLNB detection modalities comprising a blue dye, a radioactive tracer, or a combination of both have advantages as well as disadvantages. Thus, near-infrared fluorescence imaging using indocyanine green (ICG) has recently been regarded as a novel method that has generated interest for SLNB around the world. However, the lack of appropriate fluorescence imaging systems has hindered further research and wide application of this method. Therefore, we developed novel fluorescence image-guided resection equipment (FIRE) to detect sentinel lymph nodes (SLNs). Moreover, to compare the ICG fluorescence imaging method with the blue dye method and to explore the universal feasibility of the former, a different type of hospital study was conducted. Ninety-nine eligible patients participated in the study at 3 different types of hospitals. After subcutaneous ICG allergy testing, all the patients were subcutaneously injected with methylene blue and ICG into the subareolar area. Consequently, 276 SLNs (range 1-7) were identified in 98 subjects (detection rate: 99%) by using the ICG fluorescence imaging method. In contrast, the blue dye method only identified 202 SLNs (range 1-7) in 91 subjects (detection rate: 91.92%). Besides, the results of the fluorescence imaging method were similar in the 3 hospitals. Our findings indicate the universal feasibility of the ICG fluorescence imaging method for SLNB using the fluorescence image-guided resection equipment in early breast cancer detection.

Illuminating necrosis: From mechanistic exploration to preclinical application using fluorescence molecular imaging with indocyanine green

Tissue necrosis commonly accompanies the development of a wide range of serious diseases. Therefore, highly sensitive detection and precise boundary delineation of necrotic tissue via effective imaging techniques are crucial for clinical treatments; however, no imaging modalities have achieved satisfactory results to date. Although fluorescence molecular imaging (FMI) shows potential in this regard, no effective necrosis-avid fluorescent probe has been developed for clinical applications. Here, we demonstrate that indocyanine green (ICG) can achieve high avidity of necrotic tissue owing to its interaction with lipoprotein (LP) and phospholipids. The mechanism was explored at the cellular and molecular levels through a series of in vitro studies. Detection of necrotic tissue and real-time image-guided surgery were successfully achieved in different organs of different animal models with the help of FMI using in house-designed imaging devices. The results indicated that necrotic tissue with a 0.6 mm diameter could be effectively detected with precise boundary definition. We believe that the new discovery and the associated imaging techniques will improve personalized and precise surgery in the near future.

Novel l 2,1-norm optimization method for fluorescence molecular tomography reconstruction.

Fluorescence molecular tomography (FMT) is a promising tomographic method in preclinical research, which enables noninvasive real-time three-dimensional (3-D) visualization for in vivo studies. The ill-posedness of the FMT reconstruction problem is one of the many challenges in the studies of FMT. In this paper, we propose a l 2,1-norm optimization method using a priori information, mainly the structured sparsity of the fluorescent regions for FMT reconstruction. Compared to standard sparsity methods, the structured sparsity methods are often superior in reconstruction accuracy since the structured sparsity utilizes correlations or structures of the reconstructed image. To solve the problem effectively, the Nesterovs method was used to accelerate the computation. To evaluate the performance of the proposed l 2,1-norm method, numerical phantom experiments and in vivo mouse experiments are conducted. The results show that the proposed method not only achieves accurate and desirable fluorescent source reconstruction, but also demonstrates enhanced robustness to noise.